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<title>SMART: 14_3_3 domain annotation</title>

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        Letunic et al. (2017) Nucleic Acids Res doi: 10.1093/nar/gkx922Nucleic Acids Res doi: 10.1093/nar/gkaa937

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14_3_3
14-3-3 homologues

SMART accession number:	SM00101

Description:
14-3-3 homologues mediates signal transduction by binding to phosphoserine-containing proteins. They are involved in growth factor signalling and also interact with MEK kinases.

Family alignment:
<form>
<input name="NAME" value="14_3_3"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
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There are 6285 14_3_3 domains in 6269 proteins in SMART's nrdb database.

Click on the following links for more information.

Evolution (species in which this domain is found)

Taxonomic distribution of proteins containing 14_3_3 domain.

This tree includes only several representative species. The complete taxonomic breakdown of all proteins with 14_3_3 domain is also avaliable.

<input type="button" value="Expand all nodes"/> <input type="text" value="search for a taxonomic node..."/>

Proteins%Domains%

Bacteria160.26160.25

undefined kingdom160.26160.25

Eukaryota625299.73626899.47

Fungi111817.83111917.79

Metazoa285645.56286245.44

Viridiplantae176628.17176628.10

undefined kingdom5128.175218.15

undefined superkingdom10.0210.02

undefined kingdom10.0210.02

Click on the protein counts, or double click on taxonomic names to display all proteins containing 14_3_3 domain in the selected taxonomic class.

Cellular role (predicted cellular role)

Binding / catalysis: Phosphoserine-binding; homodimer formation

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

Tsukita S, Yonemura S

Cortical actin organization: lessons from ERM (ezrin/radixin/moesin) proteins.

J Biol Chem. 1999; 274: 34507-10

Yin HL, Stull JT

Proteins that regulate dynamic actin remodeling in response to membrane signaling minireview series.

J Biol Chem. 1999; 274: 32529-30

Andrews RK, Harris SJ, McNally T, Berndt MC

Binding of purified 14-3-3 zeta signaling protein to discrete amino acid sequences within the cytoplasmic domain of the platelet membrane glycoprotein Ib-IX-V complex.

Biochemistry. 1998; 37: 638-47

Display abstract

The glycoprotein (GP) Ib-IX-V complex constitutively expressed on the platelet plasma membrane mediates initial adhesion of circulating platelets to vessel wall matrix at high shear, and shear-induced platelet aggregation. In both cases, this involves binding of GP Ib-IX-V to the adhesive glycoprotein, von Willebrand Factor (vWF). vWF binding to GP Ib-IX-V rapidly induces platelet activation, leading to cytoskeletal rearrangement, shape change, and secretion that enables alphaIIbbeta3 integrin (GP IIb-IIIa)-dependent platelet aggregation. All these events are critical in (patho)physiological thrombus formation. The recent discovery that the signaling protein, 14-3-3 zeta, copurifies with the GP Ib-IX complex (minus GP V) [Du, X., Harris, S. J., Tetaz, T. J., Ginsberg, M. H., & Berndt, M. C. (1994) J. Biol. Chem. 269, 18287-18290] indicated a potential mechanism for vWF-dependent signaling. The aim of the present study was to identify discrete amino acid sequences that bind 14-3-3 zeta within the cytoplasmic domain of the receptor. As an initial screening assay, overlapping synthetic peptides based on the cytoplasmic domains of GP Ibalpha (100 residues), GP Ibbeta (34 residues), GP IX (5 residues), and GP V (16 residues) were immobilized and assessed for the ability to bind purified 14-3-3 zeta. The C-terminal sequence GHSL of GP Ibalpha was identified as one 14-3-3 zeta interactive sequence, consistent with previous results [Du, X., Fox, J. E., & Pei, S. (1996) J. Biol. Chem. 271, 7362-7367]. Binding of 125I-labeled 14-3-3 zeta to GHSL-containing peptides was inhibitable by unlabeled 14-3-3 zeta and by anti-14-3-3 zeta IgG. Ala-walking through the GHSL sequence suggested all residues were necessary for optimal binding. In addition, 14-3-3 zeta bound with lower affinity to a peptide based on the central region of the GP Ibalpha cytoplasmic domain (Arg-557-Gly-575), whereas peptide sequences within the cytoplasmic domains of GP Ibbeta (Arg-160-Arg-175) and GP V (Lys-529-Gly-544) bound 14-3-3 zeta with comparable affinity to the GHSL-containing peptide. Soluble GHSL-containing peptides, GP Ibbeta- and GP V-based peptides semidissociated 14-3-3 zeta from GP Ib-IX-V or GP Ib-IX in platelet extracts as analyzed by immunoprecipitation, suggesting these sequences, at least partially, mediate the GP Ib-IX-V-14-3-3 zeta interaction in cells. Further, phosphorylation of the GP Ibbeta peptide at a site corresponding to a protein kinase A phosphorylation site (Ser-166) enhanced the affinity of 14-3-3 zeta binding by approximately 8-fold, suggesting phosphorylation as a potential mechanism for regulating 14-3-3 zeta association with the GP Ib-IX-V complex.

Fanger GR, Widmann C, Porter AC, Sather S, Johnson GL, Vaillancourt RR

14-3-3 proteins interact with specific MEK kinases.

J Biol Chem. 1998; 273: 3476-83

Display abstract

MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase) kinases (MEKKs) regulate c-Jun N-terminal kinase and extracellular response kinase pathways. The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. 14-3-3 proteins bound both the N-terminal regulatory and C-terminal kinase domains of MEKK3. The binding affinity of 14-3-3 for the MEKK3 N terminus was 90 nM, demonstrating a high affinity interaction. 14-3-3 proteins also interacted with MEKK1 and MEKK2, but not MEKK4. Endogenous 14-3-3 protein and MEKK1 and MEKK2 were similarly distributed in the cell, consistent with their in vitro interactions. MEKK1 and 14-3-3 proteins colocalized using two-color digital confocal immunofluorescence. Binding of 14-3-3 proteins mapped to the N-terminal 393 residues of 196-kDa MEKK1. Unlike MEKK2 and MEKK3, the C-terminal kinase domain of MEKK1 demonstrated little or no ability to interact with 14-3-3 proteins. MEKK1, but not MEKK2, -3 or -4, is a caspase-3 substrate that when cleaved releases the kinase domain from the N-terminal regulatory domain. Functionally, caspase-3 cleavage of MEKK1 releases the kinase domain from the N-terminal 14-3-3-binding region, demonstrating that caspases can selectively alter protein kinase interactions with regulatory proteins. With regard to MEKK1, -2 and -3, 14-3-3 proteins do not appear to directly influence activity, but rather function as "scaffolds" for protein-protein interactions.

Kosaki A, Yamada K, Suga J, Otaka A, Kuzuya H

14-3-3beta protein associates with insulin receptor substrate 1 and decreases insulin-stimulated phosphatidylinositol 3'-kinase activity in 3T3L1 adipocytes.

J Biol Chem. 1998; 273: 940-4

Display abstract

The 14-3-3 protein family has been implicated in growth factor signaling. We investigated whether 14-3-3 protein is involved in insulin signaling in 3T3L1 adipocytes. A significant amount of insulin receptor substrate 1 (IRS-1) was immunodetected in the immunoprecipitate with anti-14-3-3beta antibody at the basal condition. 100 nM insulin increased the amount of IRS-1 in the immunoprecipitate 2.5-fold. The effect of insulin was abolished by 100 nM wortmannin. An in vitro binding study revealed that glutathione S-transferase-14-3-3beta fusion protein directly associates with recombinant IRS-1. Pretreatment of recombinant IRS-1 with alkaline phosphatase clearly decreased this association. Because the recombinant IRS-1 was not phosphorylated on its tyrosine residues, the results suggest that serine/threonine phosphorylation of IRS-1 is responsible for the association. When the cells are treated with insulin, phosphatidylinositol 3'-kinase (PI3K) is supposed to complex either 14-3-3beta-IRS-1 or IRS-1. The 14-3-3beta-IRS-1-PI3K and IRS-1-PI3K complexes were separately prepared by a sequential immunoprecipitation, first with anti-14-3-3beta and then with anti-IRS-1 antibodies. The specific activity of the PI3K in the former was approximately half of that in the latter, suggesting that 14-3-3beta protein bound to IRS-1 inhibits insulin-stimulated lipid kinase activity of PI3K in 3T3L1 adipocytes.

Shaw RJ, Henry M, Solomon F, Jacks T

RhoA-dependent phosphorylation and relocalization of ERM proteins into apical membrane/actin protrusions in fibroblasts.

Mol Biol Cell. 1998; 9: 403-19

Display abstract

The ERM proteins (ezrin, radixin, and moesin) are a group of band 4. 1-related proteins that are proposed to function as membrane/cytoskeletal linkers. Previous biochemical studies have implicated RhoA in regulating the association of ERM proteins with their membrane targets. However, the specific effect and mechanism of action of this regulation is unclear. We show that lysophosphatidic acid stimulation of serum-starved NIH3T3 cells resulted in relocalization of radixin into apical membrane/actin protrusions, which was blocked by inactivation of Rho by C3 transferase. An activated allele of RhoA, but not Rac or CDC42Hs, was sufficient to induce apical membrane/actin protrusions and localize radixin or moesin into these structures in both Rat1 and NIH3T3 cells. Lysophosphatidic acid treatment led to phosphorylation of radixin preceding its redistribution into apical protrusions. Significantly, cotransfection of RhoAV14 or C3 transferase with radixin and moesin revealed that RhoA activity is necessary and sufficient for their phosphorylation. These findings reveal a novel function of RhoA in reorganizing the apical actin cytoskeleton and suggest that this function may be mediated through phosphorylation of ERM proteins.

Xu HM, Gutmann DH

Merlin differentially associates with the microtubule and actin cytoskeleton.

J Neurosci Res. 1998; 51: 403-15

Display abstract

The neurofibromatosis 2 (NF2) suppressor gene encodes a protein termed merlin (or schwannomin) with sequence similarity to a family of proteins that link the actin cytoskeleton to cell surface glycoproteins. Members of this ERM family of proteins include ezrin, radixin, and moesin. These proteins contain a carboxyl (C-) terminus actin binding site. In contrast to the ERM proteins, merlin lacks the conventional C-terminal actin binding site, but still localizes to the ruffling edge of plasma membranes. In this study, we investigate the ability of merlin to interact with actin through a nonconventional actin binding domain. We demonstrate for the first time that merlin can associate with polymerized actin in vitro by virtue of an amino (N-) terminal actin binding domain including residues 178-367. Merlin actin binding is not affected by several naturally-occurring NF2 patient mutations or alternatively spliced isoforms. These results suggest that merlin, like other ERM proteins, can directly interact with the actin cytoskeleton. In addition, merlin associates with polymerized microtubules in vitro using a novel microtubule binding region in the N-terminal region of merlin that is masked in the full-length merlin molecule, such that wild-type functional merlin in the "closed" conformation fails to bind polymerized microtubules. These microtubule association results confirm the notion that merlin exists in "open" and "closed" conformations relevant to its function as a negative growth regulator.

Ichimura T et al.

The 14-3-3 protein binds its target proteins with a common site located towards the C-terminus.

FEBS Lett. 1997; 413: 273-6

Display abstract

The 14-3-3 protein family binds a variety of proteins in cell-signaling pathways, but the structural elements necessary for the ligand binding are poorly understood. Here we demonstrate that the 'box-1' region, which spans residues 171-213 in the eta-isoform and was previously identified as the binding site of 14-3-3 to the phosphorylated tryptophan hydroxylase, plays a critical role in the interaction with many target proteins. Using a series of truncated 14-3-3 mutants, we show that the mutant 167-213 carrying box-1 binds bacurovirus-expressed Raf-1 and Bcr protein kinases to the similar extent as the full-length 14-3-3 in a phosphorylation-dependent manner, while the mutants lacking this region abolish the binding activity. Furthermore, the box-1 region also appears essential for binding of 14-3-3 to more than 40 phosphoproteins found in the brainstem extract. These results suggest that the box-1 region, consisting of helices 7 and 8 in the tertiary structure, is a common structural element whereby the 14-3-3 protein binds many, if not all, target proteins.

Yaffe MB et al.

The structural basis for 14-3-3:phosphopeptide binding specificity.

Cell. 1997; 91: 961-71

Display abstract

The 14-3-3 family of proteins mediates signal transduction by binding to phosphoserine-containing proteins. Using phosphoserine-oriented peptide libraries to probe all mammalian and yeast 14-3-3s, we identified two different binding motifs, RSXpSXP and RXY/FXpSXP, present in nearly all known 14-3-3 binding proteins. The crystal structure of 14-3-3zeta complexed with the phosphoserine motif in polyoma middle-T was determined to 2.6 A resolution. The bound peptide is in an extended conformation, with a tight turn created by the pS +2 Pro in a cis conformation. Sites of peptide-protein interaction in the complex rationalize the peptide library results. Finally, we show that the 14-3-3 dimer binds tightly to single molecules containing tandem repeats of phosphoserine motifs, implicating bidentate association as a signaling mechanism with molecules such as Raf, BAD, and Cbl.

Jin DY, Lyu MS, Kozak CA, Jeang KT

Function of 14-3-3 proteins.

Nature. 1996; 382: 308-308

Muslin AJ, Tanner JW, Allen PM, Shaw AS

Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine.

Cell. 1996; 84: 889-97

Display abstract

The highly conserved and ubiquitously expressed 14-3-3 family of proteins bind to a variety of proteins involved in signal transduction and cell cycle regulation. The nature and specificity of 14-3-3 binding is, however, not known. Here we show that 14-3-3 is a specific phosphoserine-binding protein. Using a panel of phosphorylated peptides based on Raf-1, we have defined the 14-3-3 binding motif and show that most of the known 14-3-3 binding proteins contain the motif. Peptides containing the motif could disrupt 14-3-3 complexes and inhibit maturation of Xenopus laevis oocytes. These results suggest that the interactions of 14-3-3 with signaling proteins are critical for the activation of signaling proteins. Our findings also suggest novel roles for serine/threonine phosphorylation in the assembly of protein-protein complexes.

Nakamura H, Ozawa H

Immunolocalization of CD44 and the ERM family in bone cells of mouse tibiae.

J Bone Miner Res. 1996; 11: 1715-22

Display abstract

We studied the immunohistochemical localization of CD44, hyaluronate receptor, and the ezrin-radixin-moesin (ERM) family, actin binding proteins, in bone cells using confocal laser scanning microscopy and transmission electron microscopy to clarify the mechanism of the organization of their cytoskeletons. In osteoclasts, intense immunoreactivity to CD44 could be detected on their basolateral plasma membranes. There was less reactivity observed in the area of the plasma membrane in direct contact with the bone surface. The immunogold electron-microscopical method revealed that CD44 was mainly localized on the microvilli of the basolateral plasma membrane. The plasma membrane of the clear zone and the ruffled border were not immunolabeled with CD44. As for the ERM family, the basolateral plasma membrane of osteoclasts was stained with antimoesin monoclonal antibody, but not with ezrin or radixin. In osteoblasts attached to the bone surface, immunoreactivity to CD44 was restricted to their cytoplasmic processes. They showed immunoreactivities to radixin and moesin on the cytoplasmic side of their plasma membrane when in contact with each other. However, although osteocytes in the bone matrix demonstrate an intense immunolabeling with CD44 on their plasma membrane, they scarcely show immunoreactivity to the ERM family. These findings suggest that: (1) the CD44-moesin-actin filament system is involved in the organization of cytoskeletons in the basolateral plasma membrane of osteoclasts; and (2) other mechanisms, rather than the CD44 and the ERM family, may be involved in the cells of osteoblast lineage.

Wang W, Shakes DC

Molecular evolution of the 14-3-3 protein family.

J Mol Evol. 1996; 43: 384-98

Display abstract

Members of the highly conserved and ubiquitous 14-3-3 protein family modulate a wide variety of cellular processes. To determine the evolutionary relationships among specific 14-3-3 proteins in different plant, animal, and fungal species and to initiate a predictive analysis of isoform-specific differences in light of the latest functional and structural studies of 14-3-3, multiple alignments were constructed from forty-six 14-3-3 sequences retrieved from the GenBank and SwissProt databases and a newly identified second 14-3-3 gene from Caenorhabditis elegans. The alignment revealed five highly conserved sequence blocks. Blocks 2-5 correlate well with the alpha helices 3, 5, 7, and 9 which form the proposed internal binding domain in the three-dimensional structure model of the functioning dimer. Amino acid differences within the functional and structural domains of plant and animal 14-3-3 proteins were identified which may account for functional diversity amongst isoforms. Protein phylogenic trees were constructed using both the maximum parsimony and neighbor joining methods of the PHYLIP(3.5c) package; 14-3-3 proteins from Entamoeba histolytica, an amitochondrial protozoa, were employed as an outgroup in our analysis. Epsilon isoforms from the animal lineage form a distinct grouping in both trees, which suggests an early divergence from the other animal isoforms. Epsilons were found to be more similar to yeast and plant isoforms than other animal isoforms at numerous amino acid positions, and thus epsilon may have retained functional characteristics of the ancestral protein. The known invertebrate proteins group with the nonepsilon mammalian isoforms. Most of the current 14-3-3 isoform diversity probably arose through independent duplication events after the divergence of the major eukaryotic kingdoms. Divergence of the seven mammalian isoforms beta, zeta, gamma, eta, epsilon, tau, and sigma (stratifin/HME1) occurred before the divergence of mammalian and perhaps before the divergence of vertebrate species. A possible ancestral 14-3-3 sequence is proposed.

Zigmond SH

Signal transduction and actin filament organization.

Curr Opin Cell Biol. 1996; 8: 66-73

Display abstract

Small GTP-binding proteins of the Rho family appear to integrate extracellular signals from diverse receptor types and initiate rearrangements of F-actin. Active members of the Rho family, Rho and Rac, are now joined by Cdc42 which induces filopodia. Downstream of the Rho family proteins, actin polymerization may be induced by an increase in the availability of actin filament barbed ends. Actin organization may be affected by exposure of actin-binding sites on proteins such as vinculin and ezrin.

Cantiello HF

Role of the actin cytoskeleton on epithelial Na+ channel regulation.

Kidney Int. 1995; 48: 970-84

Display abstract

The regulatory role of actin filament organization on epithelial Na+ channel activity is reviewed in this report. The actin cytoskeleton, consisting of actin filaments and associated actin-binding proteins, is essential to various cellular events including the maintenance of cell shape, the onset of cell motility, and the distribution and stability of integral membrane proteins. Functional interactions between the actin cytoskeleton and specific membrane transport proteins are, however, not as well understood. Recent studies from our laboratory have determined that dynamic changes in the actin cytoskeletal organization may represent a novel signaling mechanism in the regulation of ion transport in epithelia. This report summarizes work conducted in our laboratory leading to an understanding of the molecular steps associated with the regulatory role of the actin-based cytoskeleton on epithelial Na+ channel function. The basis of this interaction lies on the regulation by actin-binding proteins and adjacent structures, of actin filament organization which in turn, modulates ion channel activity. The scope of this interaction may extend to such relevant cellular events as the vasopressin response in the kidney.

Friederich E, Gouin E, Hellio R, Kocks C, Cossart P, Louvard D

Targeting of Listeria monocytogenes ActA protein to the plasma membrane as a tool to dissect both actin-based cell morphogenesis and ActA function.

EMBO J. 1995; 14: 2731-44

Display abstract

Actin assembly on the surface of Listeria monocytogenes in the cytoplasm of infected cells provides a model to study actin-based motility and changes in cell shape. We have shown previously that the ActA protein, exposed on the bacterial surface, is required for polarized nucleation of actin filaments. To investigate whether plasma membrane-associated ActA can control the organization of microfilaments and cell shape, variants of ActA, in which the bacterial membrane signal had been replaced by a plasma membrane anchor sequence, were produced in mammalian cells. While both cytoplasmic and membrane-bound forms of ActA increased the F-actin content, only membrane-associated ActA caused the formation of plasma membrane extensions. This finding suggests that ActA acts as an actin filament nucleator and shows that permanent association with the inner face of the plasma membrane is required for changes in cell shape. Based on the observation that the amino-terminal segment of ActA and the remaining portion which includes the proline-rich repeats cause distinct phenotypic modifications in transfected cells, we propose a model in which two functional domains of ActA cooperate in the nucleation and dynamic turnover of actin filaments. The present approach is a new model system to dissect the mechanism of action of ActA and to further investigate interactions of the plasma membrane and the actin cytoskeleton during dynamic changes of cell shape.

Liu D, Bienkowska J, Petosa C, Collier RJ, Fu H, Liddington R

Crystal structure of the zeta isoform of the 14-3-3 protein.

Nature. 1995; 376: 191-4

Display abstract

The 14-3-3 family of proteins have recently been identified as regulatory elements in intracellular signalling pathways: 14-3-3 proteins bind to oncogene and proto-oncogene products, including c-Raf-1 (refs 2-5), c-Bcr (ref. 6) and polyomavirus middle-T antigen; overexpression of 14-3-3 activates Raf kinase in yeast and induces meiotic maturation in Xenopus oocytes. Here we report the crystal structure of the major isoform of mammalian 14-3-3 proteins at 2.9 A resolution. Each subunit of the dimeric protein consists of a bundle of nine antiparallel helices that form a palisade around an amphipathic groove. The groove is large enough to accommodate a tenth helix, and we propose that binding to an amphipathic helix represents a general mechanism for the interaction of 14-3-3 with diverse cellular proteins. The residues in the dimer interface and the putative ligand-binding surface are invariant among vertebrates, yeast and plants, suggesting a conservation of structure and function throughout the 14-3-3 family.

Xiao B et al.

Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways.

Nature. 1995; 376: 188-91

Display abstract

A broad range of organisms and tissues contain 14-3-3 proteins, which have been associated with many diverse functions including critical roles in signal transduction pathways, exocytosis and cell cycle regulation. We report here the crystal structure of the human T-cell 14-3-3 isoform (tau) dimer at 2.6 A resolution. Each monomer (Mr 28K) is composed of an unusual arrangement of nine antiparallel alpha-helices organized as two structural domains. The dimer creates a large, negatively charged channel approximately 35 A broad, 35 A wide and 20 A deep. Overall, invariant residues line the interior of this channel whereas the more variable residues are distributed on the outer surface. At the base of this channel is a 16-residue segment of 14-3-3 which has been implicated in the binding of 14-3-3 to protein kinase C.

Hitt AL, Luna EJ

Membrane interactions with the actin cytoskeleton.

Curr Opin Cell Biol. 1994; 6: 120-30

Display abstract

Recent advances have been made in our understanding of the direct binding of actin to integral membrane proteins. New information has been obtained about indirect actin-membrane associations through spectrin superfamily members and through proteins at the cytoplasmic surfaces of focal contacts and adherens junctions.

Goodlad GA, Clark CM

Actin and actin-binding proteins in plasma membranes derived from Walker 256 ascites or solid tumour cells.

Biochim Biophys Acta. 1993; 1145: 177-9

Display abstract

Plasma membranes from Walker 256 carcinoma cells grown ascitically or as a solid tumour were examined with respect to actin content, [3H]cytochalasin B-binding and the binding of 125I-labelled G-actin to membrane proteins separated by SDS-PAGE. Differences were observed both in cytochalasin B-binding to membrane actin and affinity of 125I-labelled G-actin for specific membrane proteins.

Furuhashi K, Inagaki M, Hatano S

[Functional regulation of cytoskeleton by phosphorylation: actin phosphorylation]

Seikagaku. 1992; 64: 255-9

Nairn AC, Aderem A

Calmodulin and protein kinase C cross-talk: the MARCKS protein is an actin filament and plasma membrane cross-linking protein regulated by protein kinase C phosphorylation and by calmodulin.

Ciba Found Symp. 1992; 164: 145-54

Display abstract

The myristoylated, alanine-rich C kinase (PKC) substrate (MARCKS) is a major, specific substrate of PKC that is phosphorylated during macrophage and neutrophil activation, growth factor-dependent mitogenesis and neurosecretion. MARCKS is also a calmodulin-binding protein and binding of calmodulin inhibits phosphorylation of the protein by PKC. Several recent observations from our laboratories suggest a role for MARCKS in cellular morphology and motility. First, in macrophages MARCKS is located at points of cellular adherence where actin filaments insert at the plasma membrane and is released to the cytoplasm upon activation of PKC. Second, during neutrophil chemotaxis MARCKS undergoes a cycle of release from, and reassociation with, the plasma membrane. Third, in vitro, MARCKS is an F-actin cross-linking protein whose activity is inhibited by PKC-mediated phosphorylation and by binding to calmodulin. MARCKS therefore appears to be a regulated cross-bridge between actin and the plasma membrane. Regulation of the plasma membrane-binding and actin-binding properties of MARCKS represents a convergence of the PKC and calmodulin signal transduction pathways in the control of actin cytoskeleton-plasma membrane interactions.

Hartwig JH, Kwiatkowski DJ

Actin-binding proteins.

Curr Opin Cell Biol. 1991; 3: 87-97

Display abstract

Much new information on the sequence, structure, and function of filament crosslinking, capping, and severing proteins is now known. Other significant findings include identification of a new abundant monomer-sequestering protein in platelets, and evidence that many actin-binding proteins interact with phosphoinositides and that this interaction may have metabolic consequences.

Pershina VP, Pinaev GP, Goncharova EI

[Actin interaction with the plasma membrane fraction of the cells from a suspension subline of murine L fibroblasts]

Tsitologiia. 1990; 32: 1198-204

Display abstract

Effect of plasma membranes of murine fibroblasts cultivated in suspension on actin polymerization was studied. Using low shear viscometry of actin-membrane mixtures together with the number of extractions of membranes with actin depolymerizing buffers it was found that at least two polypeptides 220 and 94 kDa may be involved into the actin filaments-plasma membrane interaction.

Shariff A, Luna EJ

Dictyostelium discoideum plasma membranes contain an actin-nucleating activity that requires ponticulin, an integral membrane glycoprotein.

J Cell Biol. 1990; 110: 681-92

Display abstract

In previous equilibrium binding studies, Dictyostelium discoideum plasma membranes have been shown to bind actin and to recruit actin into filaments at the membrane surface. However, little is known about the kinetic pathway(s) through which actin assembles at these, or other, membranes. We have used actin fluorescently labeled with N-(1-pyrenyl)iodoacetamide to examine the kinetics of actin assembly in the presence of D. discoideum plasma membranes. We find that these membranes increase the rate of actin polymerization. The rate of membrane-mediated actin polymerization is linearly dependent on membrane protein concentrations up to 20 micrograms/ml. Nucleation (the association of activated actin monomers into oligomers) appears to be the primary step of polymerization that is accelerated. A sole effect on the initial salt-induced actin conformational change (activation) is ruled out because membranes accelerate the polymerization of pre-activated actin as well as actin activated in the presence of membranes. Elongation of preexisting filaments also is not the major step of polymerization facilitated by membranes since membranes stripped of all peripheral components, including actin, increase the rate of actin assembly to about the same extent as do membranes containing small amounts of endogenous actin. Acceleration of the nucleation step by membranes also is supported by an analysis of the dependence of polymerization lag time on actin concentration. The barbed ends of membrane-induced actin nuclei are not obstructed by the membranes because the barbed end blocking agent, cytochalasin D, reduces the rate of membrane-mediated actin nucleation. Similarly, the pointed ends of the nuclei are not blocked by membranes since the depolymerization rate of gelsolin-capped actin is unchanged in the presence of membranes. These results are consistent with previous observations of lateral interactions between membranes and actin filaments. These results also are consistent with two predictions from a model based on equilibrium binding studies; i.e., that plasma membranes should nucleate actin assembly and that membrane-bound actin nuclei should have both ends free (Schwartz, M. A., and E. J. Luna. 1988. J. Cell Biol. 107:201-209). Integral membrane proteins mediate the actin nucleation activity because activity is eliminated by heat denaturation, treatment with reducing agents, or proteolysis of membranes. Activity also is abolished by solubilization with octylglucoside but is reconstituted upon removal or dilution of the detergent. Ponticulin, the major actin-binding protein in plasma membranes, appears to be necessary for nucleation activity since activity is not reconstituted from detergent extracts depleted of ponticulin.

Keresztes M

Three actin-binding proteins are developmentally regulated in rat liver plasma membranes.

FEBS Lett. 1989; 249: 51-5

Display abstract

Actin-binding membrane proteins (linking microfilaments to the cell membrane) are involved in cytoskeleton-membrane interactions which are supposed to undergo profound changes during cell proliferation and development. In this study 8 polypeptides were shown to bind F-actin directly in the liver cell membranes of mature rats. From these, the abundance of three polypeptides, of 130, 50 and 36 kDa, was observed to increase considerably during postnatal development, which indicates a developmental change in the cytoskeleton-membrane interactions.

Miller KG, Alberts BM

F-actin affinity chromatography: technique for isolating previously unidentified actin-binding proteins.

Proc Natl Acad Sci U S A. 1989; 86: 4808-12

Display abstract

We have developed stable and easy to use filamentous actin (F-actin) affinity-chromatography columns that selectively purify proteins that bind to actin filaments from cell extracts. Most traditional assays for actin-associated proteins screen for their effects on actin polymerization or actin filament crosslinking. Because our technique requires only actin-filament binding, it can identify additional types of proteins involved in the function of the actin cytoskeleton. By chromatographing extracts of several types of cells on these columns, we show that known actin-binding proteins are selectively retained as a subset of a larger group of actin-binding proteins that have not been identified previously.

St-Onge D, Gicquaud C

Evidence of direct interaction between actin and membrane lipids.

Biochem Cell Biol. 1989; 67: 297-300

Display abstract

Actin is a protein component of the cystoskeleton and is involved in cell motility. It is believed generally that actin filaments are attached to the cell membrane through an interaction with membranous actin-binding proteins. By using an in vitro system composed of liposomes and actin, we have shown that actin may also interact directly with the phospholipids of the membrane. Actin deposited at the surface of the liposome is organized in two regular patterns: a paracrystalline sheet of parallel filaments in register, or a netlike organization. These interactions of actin with membrane lipids occur only in the presence of millimolar concentrations of Mg2+. These results suggest that the interaction of the cytoskeleton with the membrane involves, at least in part, a direct association of actin with phospholipids.

Tranter MP, Sugrue SP, Schwartz MA

Evidence for a direct, nucleotide-sensitive interaction between actin and liver cell membranes.

J Cell Biol. 1989; 109: 2833-40

Display abstract

We have investigated the association of actin with membranes isolated from rat liver. A plasma membrane-enriched fraction prepared by homogenization in a low salt/CaCl2 buffer was found to contain a substantial amount of residual actin which could be removed by treatment with 1 M Na2CO3/NaHCO3, pH 10.5. Using a sedimentation binding assay that uses gelsolin to shorten actin filaments and render membrane binding saturable (Schwartz, M. A., and E. J. Luna. 1986. J. Cell Biol. 102:2067-2075), we found that membranes stripped of endogenous actin bound 125I-actin in a specific and saturable manner. Scatchard plots of binding data were linear, indicating a single class of binding sites with a Kd of 1.6 microns; 66 micrograms actin bound/mg membrane protein at saturation. Binding of actin to liver cell membranes was negligible with unstripped membranes, was competed by excess unlabeled actin, and was greatly reduced by preheating or proteolytic digestion of the membranes. Kinetic measurements showed that binding had an initial lag phase and was strongly temperature dependent. The binding of actin to liver cell membranes was also found to be competitively inhibited by ATP and other nucleotides, including the nonhydrolyzable analogue AMP-PNP. We conclude that we have reconstituted an interaction between actin and integral membrane proteins from the rat liver. This interaction exhibits a number of distinctive features which have not been observed in other actin-membrane systems.

Pershina VP, Pinaev GP, Semenova EG

[Actin interaction with the plasma membrane fraction of cells of murine fibroblast L sublines differing by growth type in culture]

Tsitologiia. 1988; 30: 582-8

Display abstract

The association between murine fibroblast L plasma membranes and actin was studied by means of low-shear viscometry of membrane-actin mixtures. Membrane fractions of 3 genetically related sublines of L cells were used differing in cytoskeleton structural organization. The suspension cell subline LS membranes showed actin gelatin activity. On the contrary, the membranes of monolayer cell sublines L-929 and LSM were seen to bind actin and to cause decrease in viscosity. Possible mechanisms of such interactions are discussed.

Brown SS, Petzold AS

Using antibodies against Dictyostelium membranes to identify an actin-binding membrane protein.

J Cell Biol. 1987; 104: 513-8

Display abstract

Polyclonal antibodies made against Dictyostelium discoideum membranes were used to block the interaction of those membranes with actin. As expected, actin interacted mostly with the internal surface of the membrane, demonstrated by the fact that whole cells could only absorb out a minor fraction of the blocking antibody. The antibody was used to show that the membrane component(s) which interacted with actin were probably integral; they could be extracted with detergent but not with solutions designed to extract peripheral membrane proteins. To identify the responsible protein(s), Western transfers of membranes were cut into fractions which were tested for their ability to absorb out the blocking activity of the antibody. We observed a single peak at a molecular weight of approximately 20,000, and thus conclude that a 20,000-mol-wt protein is a major integral membrane actin-binding protein in Dictyostelium. This approach to the identification of proteins involved in actin-membrane interaction has allowed us to make the first identification of an actin-binding membrane protein which is based on its activity in native membranes.

Barmann M, Wadsack J, Frimmer M

A 50 kDa, actin-binding protein in plasma membranes of rat hepatocytes and of rat liver tumors.

Biochim Biophys Acta. 1986; 859: 110-6

Display abstract

Plasma membranes from normal rat livers and rat liver tumors were compared by SDS-gel electrophoresis, and analyzed for actin-binding proteins by an 125I-labelled actin gel-overlay assay and by actin-affinity blotting. After treatment of rats with alpha-hexachlorocyclohexane and after induction of liver tumors by combined treatment with N-nitrosomorpholine and phenobarbital, liver plasma membranes prepared from these animals were found to be highly enriched in an actin-binding, 50 kDa polypeptide. This polypeptide seemed to be an integral protein of the plasma membrane as judged by Triton X-114-phase separation. Microsomes did not contain an actin-binding polypeptide in the 50 kDa region. Therefore, the 50 kDa protein is a candidate for interaction of actin with the liver cell plasma membrane. A possible relationship of this protein with the multi-specific, cholate transporting system of the rat liver plasma membrane is discussed.

Mooseker MS, Coleman TR, Conzelman KA

Calcium and the regulation of cytoskeletal assembly, structure and contractility.

Ciba Found Symp. 1986; 122: 232-49

Display abstract

Calcium plays a central role in the regulation of cytoskeletal assembly, structure and contractility. In the case of actin there are a number of functional classes of actin-binding proteins which confer on a given actin filament its specific function in the cell. Among these various classes of actin-binding proteins are a subset of proteins whose activity is either regulated directly or indirectly (for example, through calmodulin) by Ca2+. This includes the regulation of actin-myosin interaction, actin assembly, actin filament interaction and the formation of supramolecular cytoskeletal networks, and the interaction of actin with membranes. Examples of these various modes of Ca2+-dependent regulation of cytoskeletal structure and contractility are discussed.

Schwartz MA, Luna EJ

Binding and assembly of actin filaments by plasma membranes from Dictyostelium discoideum.

J Cell Biol. 1986; 102: 2067-75

Display abstract

The binding of native, 125I-Bolton-Hunter-labeled actin to purified Dictyostelium discoideum plasma membranes was measured using a sedimentation assay. Binding was saturable only in the presence of the actin capping protein, gelsolin. In the presence of gelsolin, the amount of actin bound at saturation to three different membrane preparations was 80, 120, and 200 micrograms/mg of membrane protein. The respective concentrations of actin at half-saturation were 8, 12, and 18 micrograms/ml. The binding curves were sigmoidal, indicating positive cooperativity at low actin concentrations. This cooperativity appeared to be due to actin-actin associations during polymerization, since phalloidin converted the curve to a hyperbolic shape. In kinetic experiments, actin added as monomers bound to membranes at a rate of 0.6 microgram ml-1 min-1, while pre-polymerized actin bound at a rate of 3.0 micrograms ml-1 min-1. Even in the absence of phalloidin, actin bound to membranes at concentrations well below the normal critical concentration. This membrane-bound actin stained with rhodamine-phalloidin and was cross-linked by m-maleimidobenzoyl succinimide ester, a bifunctional cross-linker, into multimers with the same pattern observed for cross-linked F-actin. We conclude that D. discoideum plasma membranes bind actin specifically and saturably and that these membranes organize actin into filaments below the normal critical concentration for polymerization. This interaction probably occurs between multiple binding sites on the membrane and the side of the actin filament, and may be related to the clustering of membrane proteins.

Yamamoto K

The binding of skeletal muscle C-protein to regulated actin.

FEBS Lett. 1986; 208: 123-7

Display abstract

The binding of C-protein, a component of thick filament of myofibrils, to regulated actin filaments in the presence or absence of Ca2+ was studied. The amount of C-protein bound to regulated actin filaments in the presence of Ca2+ was higher than those in the absence of Ca2+. The addition of C-protein to regulated actin caused an increase in turbidity, especially in the presence of Ca2+, and this was found to result from side-by-side association of actin filaments into bundles. In the absence of Ca2+, no actin filament bundles were formed.

Brown SS

The linkage of actin to non-erythroid membranes.

Bioessays. 1985; 3: 65-7

Fox JE

Identification of actin-binding protein as the protein linking the membrane skeleton to glycoproteins on platelet plasma membranes.

J Biol Chem. 1985; 260: 11970-7

Display abstract

Platelets have previously been shown to contain a membrane skeleton that is composed of actin filaments, actin-binding protein, and three membrane glycoproteins (GP), GP Ib, GP Ia, and a minor glycoprotein of Mr = 250,000. The present study was designed to determine how the membrane glycoproteins were linked to actin filaments. Unstimulated platelets were lysed with Triton X-100, and the membrane skeleton was isolated on sucrose density gradients or by high-speed centrifugation. The association of the membrane glycoproteins with the actin filaments was disrupted when actin-binding protein was hydrolyzed by activity of the Ca2+-dependent protease, which was active in platelet lysates upon addition of Ca2+ in the absence of leupeptin. Similarly, activation of the Ca2+-dependent protease in intact platelets by the addition of a platelet agonist also caused the membrane glycoproteins to dissociate from the membrane skeleton. Affinity-purified actin-binding protein antibodies immunoprecipitated the membrane glycoproteins from platelet lysates in which actin filaments had been removed by DNase I-induced depolymerization and high-speed centrifugation. These results demonstrate that actin-binding protein links actin filaments of the platelet membrane skeleton to three plasma membrane glycoproteins and that filaments are released from their attachment site when actin-binding protein is hydrolyzed by the Ca2+-dependent protease within intact platelets during platelet activation.

Sutoh K

[Interactions between actin and actin-binding proteins]

Tanpakushitsu Kakusan Koso. 1985; 30: 1290-300

Goodloe-Holland CM, Luna EJ

A membrane cytoskeleton from Dictyostelium discoideum. III. Plasma membrane fragments bind predominantly to the sides of actin filaments.

J Cell Biol. 1984; 99: 71-8

Display abstract

The binding between sonicated Dictyostelium discoideum plasma membrane fragments and F-actin on Sephacryl S-1000 beads was found to be competitively inhibited by myosin subfragment-1. This inhibition is MgATP-sensitive, exhibits a Ki of approximately 5 X 10(-8) M, and is reciprocal, since membranes inhibit the binding of 125I-heavy meromyosin to F-actin on beads. These experiments demonstrate that membrane binding and S-1 binding to F-actin on beads are mutually exclusive and, therefore, that the membrane fragments bind predominantly to the sides, rather than to the ends, of the actin filaments. This conclusion is supported by electron micrographs that show many lateral associations between membrane fragments and bead-associated actin filaments. Such lateral associations could play an important role in the organization and lateral movement of membrane proteins by the cytomusculature.

Therien HM, Gruda J, Carrier F

Interaction of filamentous actin with isolated liver plasma membranes.

Eur J Cell Biol. 1984; 35: 112-21

Display abstract

Actin-membrane interactions have been studied using purified liver plasma membranes and muscular filamentous actin. Despite the large quantity of endogenous actin present in membranes, exogenous muscular filamentous actin cosediments with membranes after a 30 min centrifugation at 30 000 g. The cosedimentation process is time-dependent and exhibits a complex relationship with actin concentration. The cosedimentation of actin with membranes can be partly explained by gelation as shown by low-shear viscosity and electron microscopy. The characterization of the gelation phenomenon as a function of time, actin and membrane concentrations, ionic strength, temperature and Ca2+ concentration is also presented. Gelation alone cannot however account for the overall cosedimentation data, and a more direct mode of association between actin and the membrane must be envisaged. The analogy that exists between the results obtained with liver plasma membranes and those obtained with other membrane systems suggests that a general mechanism may be involved in the interaction of actin with plasma membranes.

Burridge K, Kelly T, Connell L

Proteins involved in the attachment of actin to the plasma membrane.

Philos Trans R Soc Lond B Biol Sci. 1982; 299: 291-9

Display abstract

Proteins that may be involved in two types of actin-membrane association are discussed. The first set includes alpha-actinin, vinculin, fimbrin and a new cytoskeletal protein that are all concentrated in adhesion plaques, those regions of cultured fibroblasts where bundles of actin microfilaments terminate and where the plasma membrane comes close to the underlying substrate. The properties of non-muscle alpha-actinin suggest that it functions to cross-link actin filaments and thereby stabilize microfilament bundles rather than functioning in their attachment to the membrane. Fimbrin also appears to be involved in bundling of filaments rather than in attachment. In contrast, vinculin binds to the ends of actin filaments in vitro and is probably the best candidate for a role in the attachment of actin to membranes at the adhesion plaque. The discovery of a new protein, 215k, of unknown function, in the adhesion plaque suggests that many more proteins remain to be identified in this region. Attachment of actin filaments to other regions of the plasma membrane is also considered and a protein is described that seems to be a spectrin in brain and other tissues. The brain protein resembles erythrocyte spectrin in its physical properties, in binding actin, in being associated with cell membranes and in cross-reacting immunologically. We suggest that the brain protein and erythrocyte spectrin both belong to a family of related proteins (the spectrins) which function in the attachment of actin to membranes in many different cell types.

Lin S, Cribbs DH, Wilkins JA, Casella JF, Magargal WW, Lin DC

The capactins, a class of proteins that cap the ends of actin filaments.

Philos Trans R Soc Lond B Biol Sci. 1982; 299: 263-73

Display abstract

A number of proteins that bind specifically to the barbed ends of actin filaments in a cytochalasin-like manner have been purified to various degrees from a variety of muscle and non-muscle cells and tissues. Preliminary evidence also indicates that proteins that interact with the pointed ends of filaments are present in skeletal muscle. Because of their ability to cap one or the other end of an actin filament, we have designated this class of proteins as the 'capactins'. On the basis of their effect on actin filament assembly and interaction in vitro, we propose that the capactins play important roles in cellular regulation of actin-based cytoskeletal and contractile functions. Our finding that the disappearance of actin filament bundles in virally transformed fibroblasts can be correlated with an increase in capactin activity in the extracts of these cells is consistent with this hypothesis.

Regnouf F, Delobbe A, Gabrion J, Mesnier D, Pradel LA

Isolation from thyroid cells or purified plasma membranes with associated actin microfilaments. Proteins bound to actin.

Eur J Biochem. 1982; 122: 153-61

Display abstract

Plasma membranes of thyroid cells were purified from hog thyroid glands following two procedures. Their homogeneity was tested by electron microscopy and by measurements of the activity of membrane-bound enzyme markers. According to the procedure used the membrane fractions obtained present some differences in their morphological features as well as in the repartition of the activities of the membrane-bound enzyme markers. However, whatever the composition of the membrane fraction examined (membrane vesicles, single membrane sheets with junctional complexes), decoration with heavy meromyosin clearly shows the presence of actin filaments attached to these fragments. Analysis of proteins by polyacrylamide gel electrophoresis indicates the presence of about twelve major components with actin. Treatment of membranes with Triton X-100 results in an insoluble core which contains all the actin and most of the major proteins. The selective extraction of these components by buffers differing in their ionic strength, pH, or the presence or absence of ATP X Mg has been used to characterize some of the proteins associated to actin; among them are filamin, myosin, alpha-actinin, tropomyosin.

Wilkins JA, Lin S

High-affinity interaction of vinculin with actin filaments in vitro.

Cell. 1982; 28: 83-90

Display abstract

Immunofluorescence and microinjection experiments have shown that vinculin (molecular weight 130,000) is localized at adhesion plaques of fibroblasts spread on a solid substrate. We found that this protein affects actin filament assembly and interactions in vitro at substoichiometric levels. Vinculin inhibits the rate of actin polymerization under conditions that limit nuclei formation, indicating an effect on the filament elongation step of the reaction. Vinculin also reduces actin filament--filament interactions measured with a low-shear viscometer. Scatchard plot analysis of the binding of 3H-labeled vinculin to actin filaments showed that there is one high-affinity binding site (dissociation constant=20 nM) for every 1,500-2,000 actin monomers. These results suggested that vinculin interacts with a specific site located at the growing ends of actin filaments in a cytochalasin-like manner, a property consistent with its proposed function as a linkage protein between filaments and the plasma membranes.

Hartwig JH, Tyler J, Stossel TP

Actin-binding protein promotes the bipolar and perpendicular branching of actin filaments.

J Cell Biol. 1980; 87: 841-8

Display abstract

Branching filaments with striking perpendicularity form when actin polymerizes in the presence of macrophage actin-binding protein. Actin-binding protein molecules are visible at the branch points. Compared with actin polymerized in the absence of actin-binding proteins, not only do the filaments branch but the average length of the actin filaments decreases from 3.2 to 0.63 micrometer. Arrowhead complexes formed by addition of heavy meromyosin molecules to the branching actin filaments point toward the branch points. Actin-binding protein also accelerates the onset of actin polymerization. All of these findings show that actin filaments assemble from nucleating sites on actin-binding protein dimers. A branching polymerization of actin filaments from a preexisting lattice of actin filaments joined by actin-binding protein molecules could generate expansion of cortical cytoplasm in amoeboid cells.

Isenberg G, Aebi U, Pollard TD

An actin-binding protein from Acanthamoeba regulates actin filament polymerization and interactions.

Nature. 1980; 288: 455-9

Display abstract

A protein has been purified from Acanthamoeba which, like cytochalasin B, caps the end of actin filaments normally favoured for monomer addition and inhibits the interactions of actin filaments. In addition, this 'capping' protein nucleates the polymerization of actin monomers and blocks the annealing of actin filament fragments.

Boxer LA, Richardson S, Floyd A

Identification of actin-binding protein in membrane of polymorphonuclear leukocytes.

Nature. 1976; 263: 249-51

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description

90.20	 map04110	Cell cycle

9.80	 map04115	p53 signaling pathway

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with 14_3_3 domain which could be assigned to a KEGG orthologous group, and not all proteins containing 14_3_3 domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of 14_3_3 domains in PDB

PDB code	Main view	Title

1a37	14-3-3 PROTEIN ZETA BOUND TO PS-RAF259 PEPTIDE

1a38	14-3-3 PROTEIN ZETA BOUND TO R18 PEPTIDE

1a4o	14-3-3 PROTEIN ZETA ISOFORM

1ib1	CRYSTAL STRUCTURE OF THE 14-3-3 ZETA:SEROTONIN N-ACETYLTRANSFERASE COMPLEX

1o9c	Structural view of a fungal toxin acting on a 14-3-3 regulatory complex

1o9d	Structural view of a fungal toxin acting on a 14-3-3 regulatory complex

1o9e	Structural view of a fungal toxin acting on a 14-3-3 regulatory complex

1o9f	Structural view of a fungal toxin acting on a 14-3-3 regulatory complex

1qja	14-3-3 ZETA/PHOSPHOPEPTIDE COMPLEX (MODE 2)

1qjb	14-3-3 ZETA/PHOSPHOPEPTIDE COMPLEX (MODE 1)

1ywt	Crystal structure of the human sigma isoform of 14-3-3 in complex with a mode-1 phosphopeptide

1yz5	The crystal structure of 14-3-3-sigma at 2.8 angstrom resolution

2b05	Crystal Structure of 14-3-3 gamma in complex with a phosphoserine peptide

2bq0	14-3-3 Protein Beta (Human)

2br9	14-3-3 Protein Epsilon (Human) Complexed to Peptide

2btp	14-3-3 Protein Theta (Human) Complexed to Peptide

2c1j	Molecular basis for the recognition of phosphorylated and  phosphoacetylated histone H3 by 14-3-3

2c1n	Molecular basis for the recognition of phosphorylated and  phosphoacetylated histone H3 by 14-3-3

2c23	14-3-3 Protein Beta (Human) in complex with exoenzyme S peptide

2c63	14-3-3 Protein Eta (Human) Complexed to Peptide

2c74	14-3-3 Protein Eta (Human) Complexed to Peptide

2npm	crystal structure of Cryptosporidium parvum 14-3-3 protein in complex with peptide

2o02	Phosphorylation independent interactions between 14-3-3 and Exoenzyme S: from structure to pathogenesis

2o98	Structure of the 14-3-3 / H+-ATPase plant complex

2v7d	14-3-3 protein zeta in complex with Thr758 phosphorylated integrin  beta2 peptide

2wh0	Recognition of an intrachain tandem 14-3-3 binding site within  protein kinase C epsilon

3axy	Structure of Florigen Activation Complex Consisting of Rice Florigen Hd3a, 14-3-3 Protein GF14 and Rice FD Homolog OsFD1

3cu8	Impaired binding of 14-3-3 to Raf1 is linked to Noonan and LEOPARD syndrome

3e6y	Structure of 14-3-3 in complex with the differentiation-inducing agent Cotylenin A

3efz	Crystal Structure of a 14-3-3 protein from cryptosporidium parvum (cgd1_2980)

3iqj	Crystal Structure of human 14-3-3 sigma in Complex with Raf1 peptide (10mer)

3iqu	Crystal Structure of human 14-3-3 sigma in Complex with Raf1 peptide (6mer)

3iqv	Crystal Structure of human 14-3-3 sigma in Complex with Raf1 peptide (6mer) and stabilisator Fusicoccin

3lw1	Binary complex of 14-3-3 sigma and p53 pT387-peptide

3m50	Structure of the 14-3-3/PMA2 complex stabilized by Epibestatin

3m51	Structure of the 14-3-3/PMA2 complex stabilized by Pyrrolidone1

3mhr	14-3-3 sigma in complex with YAP pS127-peptide

3nkx	Impaired binding of 14-3-3 to Raf1 is linked to Noonan and LEOPARD syndrome

3o8i	Structure of 14-3-3 isoform sigma in complex with a C-Raf1 peptide and a stabilizing small molecule fragment

3p1n	Crystal structure of human 14-3-3 sigma in complex with TASK-3 peptide

3p1o	Crystal structure of human 14-3-3 sigma in complex with TASK-3 peptide and stabilisator Fusicoccin A

3p1p	Crystal structure of human 14-3-3 sigma C38N/N166H in complex with TASK-3 peptide

3p1q	Crystal structure of human 14-3-3 sigma C38N/N166H in complex with TASK-3 Peptide and stabilizer fusicoccin A

3p1r	Crystal structure of human 14-3-3 sigma C38V/N166H in complex with TASK-3 peptide

3p1s	Crystal structure of human 14-3-3 sigma C38N/N166H in complex with TASK-3 peptide and stabilizer fusicoccin A

3rdh	X-ray induced covalent inhibition of 14-3-3

3smk	Crystal structure of human 14-3-3 sigma C38V/N166H in complex with TASK-3 peptide and stabilizer Cotylenin A

3sml	Crystal structure of human 14-3-3 sigma C38N/N166H in complex with TASK-3 peptide and stabilizer Fusicoccin A aglycone

3smm	Crystal structure of human 14-3-3 sigma C38N/N166H in complex with task-3 peptide and stabilizer Fusicoccin J aglycone

3smn	Crystal structure of human 14-3-3 sigma C38N/N166H in complex with task-3 peptide and stabilizer Fusicoccin A-THF

3smo	Crystal structure of human 14-3-3 sigma C38V/N166H in complex with TASK-3 peptide and stabilizer Fusicoccin J aglycone

3sp5	3SP5

3spr	Crystal structure of human 14-3-3 sigma C38V/N166H in complex with TASK-3 peptide and stabilizer FC-THF

3t0l	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

3t0m	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

3u9x	Covalent attachment of pyridoxal-phosphate derivatives to 14-3-3 proteins

3ual	Crystal Structure of 14-3-3 epsilon with Mlf1 peptide

3ubw	Complex of 14-3-3 isoform epsilon, a Mlf1 phosphopeptide and a small fragment hit from a FBDD screen

3ux0	Crystal structure of human 14-3-3 sigma in complex with TASK-3 peptide and stabilizer Fusicoccin H

3uzd	Crystal structure of 14-3-3 GAMMA

4bg6	14-3-3 interaction with Rnd3 prenyl-phosphorylation motif

4dat	Structure of 14-3-3 sigma in complex with PADI6 14-3-3 binding motif II

4dau	Structure of 14-3-3 sigma in complex with PADI6 14-3-3 binding motif I

4dhm	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

4dhn	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

4dho	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

4dhp	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

4dhq	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

4dhr	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

4dhs	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

4dht	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

4dhu	Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening

4dnk	Crystal structure of a tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide (YWHAB) from homo sapiens at 2.20 A resolution.

4dx0	Structure of the 14-3-3/PMA2 complex stabilized by a pyrazole derivative

4e2e	Crystal structure of a tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, gamma polypeptide (YWHAG) from Homo sapiens at 2.25 A resolution

4f7r	Crystal structure of 14-3-3 protein from Giardia intestinalis

4fj3	14-3-3 isoform zeta in complex with a diphoyphorylated C-RAF peptide

4fl5	Crystal structure of human 14-3-3 sigma in complex with a Tau-protein peptide surrounding pS214

4fr3	Crystal structure of human 14-3-3 sigma in complex with TASK-3 peptide and stabilizer 16-O-Me-FC-H

4gnt	Complex of ChREBP and 14-3-3beta

4hkc	14-3-3-zeta in complex with S1011 phosphorylated integrin alpha-4 peptide

4hqw	Molecular tweezers modulate 14-3-3 protein-protein interactions

4hru	Molecular tweezers modulate 14-3-3 protein-protein interactions

4iea	14-3-3 isoform sigma in complex with a phosphorylated C-RAF peptide

4ihl	Human 14-3-3 isoform zeta in complex with a diphoyphorylated C-RAF peptide and Cotylenin A

4j6s	14-3-3gamma complexed with the N-terminal sequence of tyrosine hydroxylase (residues 1-43)

4jc3	14-3-3 protein interaction with Estrogen Receptor Alpha provides a novel drug target interface

4jdd	14-3-3 protein interaction with Estrogen Receptor Alpha provides a novel drug target interface

4n7g	Crystal structure of 14-3-3zeta in complex with a peptide derived from ExoS

4n7y	Crystal structure of 14-3-3zeta in complex with a 8-carbon-linker cyclic peptide derived from ExoS

4n84	Crystal structure of 14-3-3zeta in complex with a 12-carbon-linker cyclic peptide derived from ExoS

4o46	14-3-3-gamma in complex with influenza NS1 C-terminal tail phosphorylated at S228

4qli	4QLI

4wrq	4WRQ

4y32	4Y32

4y3b	4Y3B

4y5i	4Y5I

4zdr	4ZDR

4zq0	4ZQ0

5btv	5BTV

5by9	5BY9

5d2d	5D2D

5d3e	5D3E

5d3f	5D3F

5ewz	5EWZ

5exa	5EXA

5f74	5F74

5hf3	5HF3

5iqp	5IQP

5j31	5J31

5lho	5LHO

5lvz	5LVZ

5lx2	5LX2

Links (links to other resources describing this domain)

INTERPRO	IPR023410

PFAM	14-3-3

4.1m
putative band 4.1 homologues' binding motif

SMART accession number:	SM00294

Description:
 -

Family alignment:
<form>
<input name="NAME" value="4.1m"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

acidPPc
Acid phosphatase homologues

SMART accession number:	SM00014

Description:
 -

Family alignment:
<form>
<input name="NAME" value="acidPPc"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

ADF
Actin depolymerisation factor/cofilin -like domains

SMART accession number:	SM00102

Description:
Severs actin filaments and binds to actin monomers.

GO function:	actin binding (GO:0003779)

Family alignment:
<form>
<input name="NAME" value="ADF"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

ANK
ankyrin repeats

SMART accession number:	SM00248

Description:
Ankyrin repeats are about 33 amino acids long and occur in at least four consecutive copies. They are involved in protein-protein interactions. The core of the repeat seems to be an helix-loop-helix structure.

GO function:	protein binding (GO:0005515)

Family alignment:
<form>
<input name="NAME" value="ANK"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

APCDDC
Adenomatosis polyposis coli down-regulated 1

SMART accession number:	SM01352

Description:
The domain is duplicated in most members of this family. APCDD is directly regulated by the beta-catenin/Tcf complex, and its elevated expression promotes proliferation of colonic epithelial cells in vitro and in vivo (PMID:12384519). APCDD1 has an N-terminal signal-peptide and a C-terminal transmembrane region. The domain is rich in cysteines, there being up to 12 such residues, a structural motif important for interaction between Wnt ligands and their receptors. APCDD1 is expressed in a broad repertoire of cell types, indicating that it may regulate a diverse range of biological processes controlled by Wnt signalling (PMID:20393562).

Family alignment:
<form>
<input name="NAME" value="APCDDC"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

ARF
ARF-like small GTPases; ARF, ADP-ribosylation factor

SMART accession number:	SM00177

Description:
Ras homologues involved in vesicular transport. Activator of phospholipase D isoforms. Unlike Ras proteins they lack cysteine residues at their C-termini and therefore are unlikely to be prenylated. ARFs are N-terminally myristoylated. Contains ATP/GTP-binding motif (P-loop).

Family alignment:
<form>
<input name="NAME" value="ARF"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

ArfGap
Putative GTP-ase activating proteins for the small GTPase, ARF

SMART accession number:	SM00105

Description:
Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.

GO function:	GTPase activator activity (GO:0005096)

Family alignment:
<form>
<input name="NAME" value="ArfGap"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

ARM
Armadillo/beta-catenin-like repeats

SMART accession number:	SM00185

Description:
Approx. 40 amino acid repeat. Tandem repeats form superhelix of helices that is proposed to mediate interaction of beta-catenin with its ligands. Involved in transducing the Wingless/Wnt signal. In plakoglobin arm repeats bind alpha-catenin and N-cadherin.

GO function:	protein binding (GO:0005515)

Family alignment:
<form>
<input name="NAME" value="ARM"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

B41
Band 4.1 homologues

SMART accession number:	SM00295

Description:
Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

Family alignment:
<form>
<input name="NAME" value="B41"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

B561
Cytochrome b-561 / ferric reductase transmembrane domain.

SMART accession number:	SM00665

Description:
Cytochrome b-561 recycles ascorbate for the generation of norepinephrine by dopamine-beta-hydroxylase in the chromaffin vesicles of the adrenal gland. It is a transmembrane heme protein with the two heme groups being bound to conserved histidine residues. A cytochrome b-561 homologue, termed Dcytb, is an iron-regulated ferric reductase in the duodenal mucosa. Other homologues of these are also likely to be ferric reductases. SDR2 is proposed to be important in regulating the metabolism of iron in the onset of neurodegenerative disorders.

Family alignment:
<form>
<input name="NAME" value="B561"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

B_lectin
Bulb-type mannose-specific lectin

SMART accession number:	SM00108

Description:
 -

Family alignment:
<form>
<input name="NAME" value="B_lectin"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

BAG
BAG domains, present in regulator of Hsp70 proteins

SMART accession number:	SM00264

Description:
BAG domains, present in Bcl-2-associated athanogene 1 and silencer of death domains

GO function:	chaperone binding (GO:0051087)

Family alignment:
<form>
<input name="NAME" value="BAG"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

BH4
BH4 Bcl-2 homology region 4

SMART accession number:	SM00265

Description:
 -

GO process:	regulation of apoptotic process (GO:0042981)

Family alignment:
<form>
<input name="NAME" value="BH4"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

BIR
Baculoviral inhibition of apoptosis protein repeat

SMART accession number:	SM00238

Description:
Domain found in inhibitor of apoptosis proteins (IAPs) and other proteins. Acts as a direct inhibitor of caspase enzymes.

Family alignment:
<form>
<input name="NAME" value="BIR"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

BTK
Bruton's tyrosine kinase Cys-rich motif

SMART accession number:	SM00107

Description:
Zinc-binding motif containing conserved cysteines and a histidine. Always found C-terminal to PH domains (but not all PH domains are followed by BTK motifs). The crystal structure shows this motif packs against the PH domain. The PH+Btk module pair has been called the Tec homology (TH) region.

GO process:	intracellular signal transduction (GO:0035556)

Family alignment:
<form>
<input name="NAME" value="BTK"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

C1
Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains)

SMART accession number:	SM00109

Description:
Some bind phorbol esters and diacylglycerol. Some bind RasGTP. Zinc-binding domains.

GO process:	intracellular signal transduction (GO:0035556)

Family alignment:
<form>
<input name="NAME" value="C1"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

C2
Protein kinase C conserved region 2 (CalB)

SMART accession number:	SM00239

Description:
Ca2+-binding motif present in phospholipases, protein kinases C, and synaptotagmins (among others). Some do not appear to contain Ca2+-binding sites. Particular C2s appear to bind phospholipids, inositol polyphosphates, and intracellular proteins. Unusual occurrence in perforin. Synaptotagmin and PLC C2s are permuted in sequence with respect to N- and C-terminal beta strands. SMART detects C2 domains using one or both of two profiles.

Family alignment:
<form>
<input name="NAME" value="C2"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

Calx_beta
Domains in Na-Ca exchangers and integrin-beta4

SMART accession number:	SM00237

Description:
Domain in Na-Ca exchangers and integrin subunit beta4 (and some cyanobacterial proteins)

GO process:	cell communication (GO:0007154)

GO component:	integral component of membrane (GO:0016021)

Family alignment:
<form>
<input name="NAME" value="Calx_beta"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

CARD
Caspase recruitment domain

SMART accession number:	SM00114

Description:
Motif contained in proteins involved in apoptotic signalling. Mediates homodimerisation. Structure consists of six antiparallel helices arranged in a topology homologue to the DEATH and the DED domain.

GO process:	regulation of apoptotic process (GO:0042981)

Family alignment:
<form>
<input name="NAME" value="CARD"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

CASc
Caspase, interleukin-1 beta converting enzyme (ICE) homologues

SMART accession number:	SM00115

Description:
Cysteine aspartases that mediate programmed cell death (apoptosis). Caspases are synthesised as zymogens and activated by proteolysis of the peptide backbone adjacent to an aspartate. The resulting two subunits associate to form an (alpha)2(beta)2-tetramer which is the active enzyme. Activation of caspases can be mediated by other caspase homologues.

GO function:	cysteine-type peptidase activity (GO:0008234)

Family alignment:
<form>
<input name="NAME" value="CASc"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

CH
Calponin homology domain

SMART accession number:	SM00033

Description:
Actin binding domains present in duplicate at the N-termini of spectrin-like proteins (including dystrophin, alpha-actinin). These domains cross-link actin filaments into bundles and networks. A calponin homology domain is predicted in yeasst Cdc24p.

GO function:	protein binding (GO:0005515)

Family alignment:
<form>
<input name="NAME" value="CH"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

CheW
Two component signalling adaptor domain

SMART accession number:	SM00260

Description:
 -

GO process:	signal transduction (GO:0007165), chemotaxis (GO:0006935)

Family alignment:
<form>
<input name="NAME" value="CheW"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

CNH
Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2

SMART accession number:	SM00036

Description:
Unpublished observations.

Family alignment:
<form>
<input name="NAME" value="CNH"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

cNMP
Cyclic nucleotide-monophosphate binding domain

SMART accession number:	SM00100

Description:
Catabolite gene activator protein (CAP) is a prokaryotic homologue of eukaryotic cNMP-binding domains, present in ion channels, and  cNMP-dependent kinases.

Family alignment:
<form>
<input name="NAME" value="cNMP"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

CULLIN
Cullin

SMART accession number:	SM00182

Description:
 -

Family alignment:
<form>
<input name="NAME" value="CULLIN"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

CYCc
Adenylyl- / guanylyl cyclase, catalytic domain

SMART accession number:	SM00044

Description:
Present in two copies in mammalian adenylyl cyclases. Eubacterial homologues are known. Two residues (Asn, Arg) are thought to be involved in catalysis. These cyclases have important roles in a diverse range of cellular processes.

GO process:	cyclic nucleotide biosynthetic process (GO:0009190), intracellular signal transduction (GO:0035556)

Family alignment:
<form>
<input name="NAME" value="CYCc"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

Cyclin_C

SMART accession number:	SM01332

Description:
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase (Cdk) enzymes.

Family alignment:
<form>
<input name="NAME" value="Cyclin_C"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

Cyt-b5
Cytochrome b5-like Heme/Steroid binding domain

SMART accession number:	SM01117

Description:
This family includes heme binding domains from a diverse range of proteins. This family also includes proteins that bind to steroids. The family includes progesterone receptors such as O00264 ((PUBMED:9705155),(PUBMED:8774719)). Many members of this subfamily are membrane anchored by an N-terminal transmembrane alpha helix. This family also includes a domain in some chitin synthases. There is no known ligand for this domain in the chitin synthases.

Family alignment:
<form>
<input name="NAME" value="Cyt-b5"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

DAGKa
Diacylglycerol kinase accessory domain (presumed)

SMART accession number:	SM00045

Description:
Diacylglycerol (DAG) is a second messenger that acts as a protein kinase C activator. DAG can be produced from the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by a phosphoinositide-specific phospholipase C and by the degradation of phosphatidylcholine (PC) by a phospholipase C or the concerted actions of phospholipase D and phosphatidate phosphohydrolase. This domain might either be an accessory domain or else contribute to the catalytic domain. Bacterial homologues are known.

GO process:	protein kinase C-activating G protein-coupled receptor signaling pathway (GO:0007205)

GO function:	diacylglycerol kinase activity (GO:0004143)

Family alignment:
<form>
<input name="NAME" value="DAGKa"/>
    View <input name="DO_CONSENSUS" type="submit" value="Alignment consensus sequence"/> or
    <input name="SHOW_ALIGNMENT" type="submit" value="Family alignment in"/>
<select name="FORMAT"><option value="CHROMA">CHROMA format</option><option value="LOGO">HMM/Web logo</option><option value="CLUSTAL">CLUSTALW format</option><option value="MSF">MSF format</option><option value="FASTA">FASTA format</option><option value="PIR">PIR format</option>
</select></form>

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```

[TARGET INFORMATION]
Based on the HTML webpage above about Proteins, extract the following properties from the items listed on the webpage: (1) Title; (2) Subtitle; (3) Smart accession number; (4) Description
Only extract the rows where the description is not empty i.e. the description is not "-".

[OUTPUT FORMAT]
Structure your output in TSV format such that each row of your output corresponds to the aforementioned properties of an item and each property is separated from each other by a tab "\t". Your output should be in the following format:
```tsv
title	subtitle	smart_accession_number	description
{Your TSV output}
```

[IMPORTANT NOTES]
- Make sure that you have read through all items listed on the webpage and followed the same order as they appear on the webpage.
- If you are asked to only extract some rows that satisfy specific conditions, ONLY extract those rows that satisfy the conditions and do NOT include other irrelevant rows in your output.
- If a property of an item is blank, not applicable, or not parseable, please set the property to "N/A" for the item.
- If a property spans multiple lines, please extract all the lines and replace the newline character with a space character.
- If a property consists of a list of items, please replace the newline character with a space character and separate the items with a comma ",".
- If there are any special characters, numerical values of a specific format, or any unusual formatting in the property, please keep them as they are. If the property comes with a unit, please keep the unit as well in the property.
- Do not include html tags in the extracted information. Only include the text.
- Do not provide any additional information in your output other than the tsv.

Now, extract the information from the HTML webpage above and follow the output format above in your answer.

title	subtitle	smart_accession_number	description
14_3_3	14-3-3 homologues	SM00101	14-3-3 homologues mediates signal transduction by binding to phosphoserine-containing proteins. They are involved in growth factor signalling and also interact with MEK kinases.
ADF	Actin depolymerisation factor/cofilin -like domains	SM00102	Severs actin filaments and binds to actin monomers.
ANK	ankyrin repeats	SM00248	Ankyrin repeats are about 33 amino acids long and occur in at least four consecutive copies. They are involved in protein-protein interactions. The core of the repeat seems to be an helix-loop-helix structure.
APCDDC	Adenomatosis polyposis coli down-regulated 1	SM01352	The domain is duplicated in most members of this family. APCDD is directly regulated by the beta-catenin/Tcf complex, and its elevated expression promotes proliferation of colonic epithelial cells in vitro and in vivo (PMID:12384519). APCDD1 has an N-terminal signal-peptide and a C-terminal transmembrane region. The domain is rich in cysteines, there being up to 12 such residues, a structural motif important for interaction between Wnt ligands and their receptors. APCDD1 is expressed in a broad repertoire of cell types, indicating that it may regulate a diverse range of biological processes controlled by Wnt signalling (PMID:20393562).
ARF	-like small GTPases; , ADP-ribosylation factor	SM00177	Ras homologues involved in vesicular transport. Activator of phospholipase D isoforms. Unlike Ras proteins they lack cysteine residues at their C-termini and therefore are unlikely to be prenylated. ARFs are N-terminally myristoylated. Contains ATP/GTP-binding motif (P-loop).
ArfGap	Putative GTP-ase activating proteins for the small GTPase, ARF	SM00105	Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.
ARM	Armadillo/beta-catenin-like repeats	SM00185	Approx. 40 amino acid repeat. Tandem repeats form superhelix of helices that is proposed to mediate interaction of beta-catenin with its ligands. Involved in transducing the Wingless/Wnt signal. In plakoglobin arm repeats bind alpha-catenin and N-cadherin.
B41	Band 4.1 homologues	SM00295	Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.
B561	Cytochrome b-561 / ferric reductase transmembrane domain.	SM00665	Cytochrome b-561 recycles ascorbate for the generation of norepinephrine by dopamine-beta-hydroxylase in the chromaffin vesicles of the adrenal gland. It is a transmembrane heme protein with the two heme groups being bound to conserved histidine residues. A cytochrome b-561 homologue, termed Dcytb, is an iron-regulated ferric reductase in the duodenal mucosa. Other homologues of these are also likely to be ferric reductases. SDR2 is proposed to be important in regulating the metabolism of iron in the onset of neurodegenerative disorders.
BAG	domains, present in regulator of Hsp70 proteins	SM00264	BAG domains, present in Bcl-2-associated athanogene 1 and silencer of death domains
BIR	Baculoviral inhibition of apoptosis protein repeat	SM00238	Domain found in inhibitor of apoptosis proteins (IAPs) and other proteins. Acts as a direct inhibitor of caspase enzymes.
BTK	Bruton's tyrosine kinase Cys-rich motif	SM00107	Zinc-binding motif containing conserved cysteines and a histidine. Always found C-terminal to PH domains (but not all PH domains are followed by BTK motifs). The crystal structure shows this motif packs against the PH domain. The PH+Btk module pair has been called the Tec homology (TH) region.
C1	Protein kinase C conserved region 1 () domains (Cysteine-rich domains)	SM00109	Some bind phorbol esters and diacylglycerol. Some bind RasGTP. Zinc-binding domains.
C2	Protein kinase C conserved region 2 (CalB)	SM00239	Ca2+-binding motif present in phospholipases, protein kinases C, and synaptotagmins (among others). Some do not appear to contain Ca2+-binding sites. Particular C2s appear to bind phospholipids, inositol polyphosphates, and intracellular proteins. Unusual occurrence in perforin. Synaptotagmin and PLC C2s are permuted in sequence with respect to N- and C-terminal beta strands. SMART detects C2 domains using one or both of two profiles.
Calx_beta	Domains in Na-Ca exchangers and integrin-beta4	SM00237	Domain in Na-Ca exchangers and integrin subunit beta4 (and some cyanobacterial proteins)
CARD	Caspase recruitment domain	SM00114	Motif contained in proteins involved in apoptotic signalling. Mediates homodimerisation. Structure consists of six antiparallel helices arranged in a topology homologue to the DEATH and the DED domain.
CASc	Caspase, interleukin-1 beta converting enzyme (ICE) homologues	SM00115	Cysteine aspartases that mediate programmed cell death (apoptosis). Caspases are synthesised as zymogens and activated by proteolysis of the peptide backbone adjacent to an aspartate. The resulting two subunits associate to form an (alpha)2(beta)2-tetramer which is the active enzyme. Activation of caspases can be mediated by other caspase homologues.
CH	Calponin homology domain	SM00033	Actin binding domains present in duplicate at the N-termini of spectrin-like proteins (including dystrophin, alpha-actinin). These domains cross-link actin filaments into bundles and networks. A calponin homology domain is predicted in yeasst Cdc24p.
CNH	Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2	SM00036	Unpublished observations.
cNMP	Cyclic nucleotide-monophosphate binding domain	SM00100	Catabolite gene activator protein (CAP) is a prokaryotic homologue of eukaryotic cNMP-binding domains, present in ion channels, and cNMP-dependent kinases.
CYCc	Adenylyl- / guanylyl cyclase, catalytic domain	SM00044	Present in two copies in mammalian adenylyl cyclases. Eubacterial homologues are known. Two residues (Asn, Arg) are thought to be involved in catalysis. These cyclases have important roles in a diverse range of cellular processes.
Cyclin_C	N/A	SM01332	Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase (Cdk) enzymes.
Cyt-b5	Cytochrome b5-like Heme/Steroid binding domain	SM01117	This family includes heme binding domains from a diverse range of proteins. This family also includes proteins that bind to steroids. The family includes progesterone receptors such as O00264 ((PUBMED:9705155),(PUBMED:8774719)). Many members of this subfamily are membrane anchored by an N-terminal transmembrane alpha helix. This family also includes a domain in some chitin synthases. There is no known ligand for this domain in the chitin synthases.
DAGKa	Diacylglycerol kinase accessory domain (presumed)	SM00045	Diacylglycerol (DAG) is a second messenger that acts as a protein kinase C activator. DAG can be produced from the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by a phosphoinositide-specific phospholipase C and by the degradation of phosphatidylcholine (PC) by a phospholipase C or the concerted actions of phospholipase D and phosphatidate phosphohydrolase. This domain might either be an accessory domain or else contribute to the catalytic domain. Bacterial homologues are known.