l2
SMART MODE:

NORMAL GENOMIC

SMART

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

14_3_3

14-3-3 homologues
14_3_3
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.
Interpro abstract (IPR023410):

The 14-3-3 proteins are a large family of approximately 30kDa acidic proteins which exist primarily as homo- and heterodimers within all eukaryotic cells [ (PUBMED:1671102) (PUBMED:11911880) ]. There is a high degree of sequence identity and conservation between all the 14-3-3 isotypes, particularly in the regions which form the dimer interface or line the central ligand binding channel of the dimeric molecule. Each 14-3-3 protein sequence can be roughly divided into three sections: a divergent amino terminus, the conserved core region and a divergent carboxyl terminus. The conserved middle core region of the 14-3-3s encodes an amphipathic groove that forms the main functional domain, a cradle for interacting with client proteins. The monomer consists of nine helices organised in an antiparallel manner, forming an L-shaped structure. The interior of the L-structure is composed of four helices: H3 and H5, which contain many charged and polar amino acids, and H7 and H9, which contain hydrophobic amino acids. These four helices form the concave amphipathic groove that interacts with target peptides.

The 14-3-3 proteins mainly bind proteins containing phosphothreonine or phosphoserine motifs, however exceptions to this rule do exist. Extensive investigation of the 14-3-3 binding site of the mammalian serine/threonine kinase Raf-1 has produced a consensus sequence for 14-3-3-binding, RSxpSxP (in the single-letter amino-acid code, where x denotes any amino acid and p indicates that the next residue is phosphorylated). The 14-3-3 proteins appear to effect intracellular signalling in one of three ways - by direct regulation of the catalytic activity of the bound protein, by regulating interactions between the bound protein and other molecules in the cell by sequestration or modification or by controlling the subcellular localisation of the bound ligand. Proteins appear to initially bind to a single dominant site and then subsequently to many, much weaker secondary interaction sites. The 14-3-3 dimer is capable of changing the conformation of its bound ligand whilst itself undergoing minimal structural alteration.

This entry represents the structural domain found in 14-3-3 proteins.

Family alignment:
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There are 6285 14_3_3 domains in 6269 proteins in SMART's nrdb database.

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4.1m

putative band 4.1 homologues' binding motif
4.1m
SMART accession number:SM00294
Description: -
Interpro abstract (IPR003585):

The putative band 4.1 homologues' binding motif is found in neurexins, syndecans and glycophorin C intracellular C-termini. Syndecans are cell surface proteoglycans and glycophorin C is a minor sialoglycoprotein in human erythrocyte membranes, which play an important role in regulating the stability of red cells.

Syndecan-4, a transmembrane heparan sulphate proteoglycan, is a coreceptor with integrins in cell adhesion. It has been suggested to form a ternary signalling complex with protein kinase Calpha and phosphatidylinositol 4,5-bisphosphate (PIP2). Structural studies have demonstrated that the cytoplasmic domain undergoes a conformational transition and forms a symmetric dimer in the presence of phospholipid activator PIP2, and whose overall structure in solution exhibits a twisted clamp shape having a cavity in the centre of dimeric interface. In addition, it has been observed that the syndecan-4 variable domain interacts, strongly, not only with fatty acyl groups but also the anionic head group of PIP2. These findings indicate that PIP2 promotes oligomerisation of the syndecan-4 cytoplasmic domain for transmembrane signalling and cell-matrix adhesion [ (PUBMED:9582338) (PUBMED:11456484) ].

Some of the proteins in this group are responsible for the molecular basis of the blood group antigens, surface markers on the outside of the red blood cell membrane. Most of these markers are proteins, but some are carbohydrates attached to lipids or proteins [Reid M.E., Lomas-Francis C. The Blood Group Antigen FactsBook Academic Press, London / San Diego, (1997)]. Glycophorin C (PAS-2') belongs to the Gerbich blood group system and is associated with An(a), Dh(A), Ls(a) and Wb antigens.

Family alignment:
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acidPPc

Acid phosphatase homologues
acidPPc
SMART accession number:SM00014
Description: -
Interpro abstract (IPR000326):

This entry represents type 2 phosphatidic acid phosphatase (PAP2; EC 3.1.3.4 ) enzymes, such as phosphatidylglycerophosphatase B EC 3.1.3.27 from Escherichia coli. PAP2 enzymes have a core structure consisting of a 5-helical bundle, where the beginning of the third helix binds the cofactor [ (PUBMED:10835340) ]. PAP2 enzymes catalyse the dephosphorylation of phosphatidate, yielding diacylglycerol and inorganic phosphate [ (PUBMED:17079146) ]. In eukaryotic cells, PAP activity has a central role in the synthesis of phospholipids and triacylglycerol through its product diacylglycerol, and it also generates and/or degrades lipid-signalling molecules that are related to phosphatidate.

Other related enzymes have a similar core structure, including haloperoxidases such as bromoperoxidase (contains one core bundle, but forms a dimer), chloroperoxidases (contains two core bundles arranged as in other family dimers), bacitracin transport permease from Bacillus licheniformis, glucose-6-phosphatase from rat. The vanadium-dependent haloperoxidases exclusively catalyse the oxidation of halides, and act as histidine phosphatases, using histidine for the nucleophilic attack in the first step of the reaction [ (PUBMED:12447906) ]. Amino acid residues involved in binding phosphate/vanadate are conserved between the two families, supporting a proposal that vanadium passes through a tetrahedral intermediate during the reaction mechanism.

Family alignment:
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ADF

Actin depolymerisation factor/cofilin -like domains
ADF
SMART accession number:SM00102
Description: Severs actin filaments and binds to actin monomers.
Interpro abstract (IPR002108):

The actin-depolymerising factor homology (ADF-H) domain is an ~150-amino acid motif that is present in three phylogenetically distinct classes of eukaryotic actin-binding proteins [ (PUBMED:9693358) (PUBMED:12207032) (PUBMED:9047337) ]:

  • ADF/cofilins, which include ADF, cofilin, destrin, actophorin, coactosin, depactin and glia maturation factors (GMFs) beta and gamma. ADF/cofilins are small actin-binding proteins composed of a single ADF-H domain. They bind both actin-monomers and filaments and promote rapid filament turnover in cells by depolymerising/fragmenting actin filaments. ADF/cofilins bind ADP-actin with higher affinity than ATP-actin and inhibit the spontaneous nucleotide exchange on actin monomers
  • Twinfilins, which are actin monomer-binding proteins that are composed of two ADF-H domains
  • Abp1/Drebrins, which are relatively large proteins composed of an N-terminal ADF-H domain followed by a variable region and a C-terminal SH3 domain. Abp1/Drebrins interact only with actin filaments and do not promote filament depolymerisation or fragmentation

Although these proteins are biochemically distinct and play different roles in actin dynamics, they all appear to use the ADF-H domain for their interactions with actin.

The ADF-H domain consists of a six-stranded mixed beta-sheet in which the four central strands (beta2-beta5) are anti-parallel and the two edge strands (beta1 and beta6) run parallel with the neighbouring strands. The sheet is surrounded by two alpha-helices on each side [ (PUBMED:9693358) (PUBMED:12207032) (PUBMED:15522287) ].

GO function:actin binding (GO:0003779)
Family alignment:
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ANK

ankyrin repeats
ANK
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.
Interpro abstract (IPR002110):

The ankyrin repeat is one of the most common protein-protein interaction motifs in nature. Ankyrin repeats are tandemly repeated modules of about 33 amino acids. They occur in a large number of functionally diverse proteins mainly from eukaryotes. The few known examples from prokaryotes and viruses may be the result of horizontal gene transfers. The repeat has been found in proteins of diverse function such as transcriptional initiators, cell-cycle regulators [ (PUBMED:31000436) ], cytoskeletal, ion transporters and signal transducers [ (PUBMED:29769718) (PUBMED:8108379) ]. The ankyrin fold appears to be defined by its structure rather than its function since there is no specific sequence or structure which is universally recognised by it.

The conserved fold of the ankyrin repeat unit is known from several crystal and solution structures [ (PUBMED:8875926) (PUBMED:9353127) (PUBMED:9461436) (PUBMED:9865693) ]. Each repeat folds into a helix-loop-helix structure with a beta-hairpin/loop region projecting out from the helices at a 90 o angle. The repeats stack together to form an L-shaped structure [ (PUBMED:8875926) (PUBMED:12461176) ].

GO function:protein binding (GO:0005515)
Family alignment:
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APCDDC

Adenomatosis polyposis coli down-regulated 1
APCDDC
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).
Interpro abstract (IPR029405):

APCDD1 is directly regulated by the beta-catenin/Tcf complex, and its elevated expression promotes proliferation of colonic epithelial cells in vitro and in vivo [ (PUBMED:12384519) ]. APCDD1 has an N-terminal signal-peptide and a C-terminal transmembrane region. This domain is duplicated in most members of the family. 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 [ (PUBMED:20393562) ].

Family alignment:
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ARF

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