ASAPs (ASAP1, ASAP2, and ASAP3) function as Arf-specific GTPase-activating proteins (GAPs), participate in rhodopsin trafficking, are associated with tumour cell metastasis, modulate phagocytosis, promote cell proliferation, facilitate vesicle budding, Golgi exocytosis, and regulate vesicle coat assembly via a Bin/Amphiphysin/Rvs domain [, , ]. Each member has a BAR, PH, Arf GAP, Ank repeat and proline rich domains. ASAP1 and ASAP2 also have a SH3 domain at the C terminus []. The ASAP family is named for the first identified member, ASAP1 [].
Ankyrin repeat and fibronectin type-III domain-containing protein 1 (ANKFN1) is an uncharacterized protein containing two ANK repeats and a fibronectin type-III domain. Homologues are known from metazoa.
This family consists of several progressive ankylosis protein (ANK or ANKH) sequences. The ANK protein spans the outer cell membrane and shuttles inorganic pyrophosphate (PPi), a major inhibitor of physiologic and pathologic calcification, bone mineralisation and bone resorption []. Mutations in ANK are thought to give rise to Craniometaphyseal dysplasia (CMD) which is a rare skeletal disorder characterised by progressive thickening and increased mineral density of craniofacial bones and abnormally developed metaphyses in long bones [].
This entry represents the SH2 domain found in Drosophila shark protein and hydra protein HTK16. Shark and HTK16 are non-receptor protein-tyrosine kinases contain two SH2 domains, five ankyrin (ANK)-like repeats, and a potential tyrosine phosphorylation site in the carboxyl-terminal tail which resembles the phosphorylation site in members of the src family. Like, mammalian non-receptor protein-tyrosine kinases, ZAP-70 and syk proteins, they do not have SH3 domains. However, the presence of ANK makes these unique among protein-tyrosine kinases. Both tyrosine kinases and ANK repeats have been shown to transduce developmental signals, and SH2 domains are known to participate intimately in tyrosine kinase signaling [].Drosophila Shark transduces intracellularly the Crumbs, a protein necessary for proper organization of ectodermal epithelia, intercellular signal []. It is essential for Draper-mediated signalling [].
This entry represents the SH3 domain of ASAP2 (Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 2). ASAP2 (Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 2; also known as AMAP2 or PAG3) is a PH domain-containing ArfGAP. It mediates the functions of Arf GTPases via dual mechanisms: it exhibits GTPase activating protein (GAP) activity towards class I (Arf1) and II (Arf5) Arfs; and it binds class III Arfs (GTP-Arf6) stably without GAP activity []. It binds paxillin and is implicated in Fcgamma receptor-mediated phagocytosis in macrophages and in cell migration []. ASAP2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain.ArfGAPs are a protein family containing the ArfGAP domain. There are 31 genes encoding ArfGAPs in human []. They catalyse the hydrolysis of GTP that is bound to Arf, thereby converting Arf-GTP to Arf-GDP [].
The Arf GAPs (GTPase-activating proteins) are a family of multidomain proteins with the common function of accelerating the hydrolysis of GTP bound to Arf proteins. ASAP proteins are a subtype of Arf GAPs. ASAP3 (Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 3), also known as DDEFL1 (development and differentiation-enhancing factor-like 1) or ACAP4, is a focal adhesion-associated Arf GAP that functions in cell migration and invasion of cancers [, ]. ASAP3 promotes cell proliferation [].
ASAP1 is an Arf GAP that associates with and regulates actin-based structures. It is also involved in actin remodeling affecting cell spreading and cell migration []. ASAP1 contains BAR, PH, Arf GAP, Ank repeats, Proline-rich, E/DLPPKP repeat, and SH3 domains. It binds to focal adhesion kinase (FAK) via its SH3 domain []. The BAR domain of ASAP1 is also critical for its cellular function in regulation of actin-based structures [].This entry includes the SH3 domain of ASAP1.
Tankyrase-1 (TANK1) is a poly-ADP-ribosyltransferase involved in various processes, including the Wnt signaling pathway, telomere length regulation and vesicle trafficking [, , , ]. In telomere length regulation and sister chromatid separation, it binds to the N terminus of telomeric TERF1 via the ANK repeats []. It binds to the RXXPDG motif in the carboxy terminal domain of NuMA, which play an essential role in mitotic spindle assembly []. It also binds to the RXXPDG motif in the cytoplasmic tail of IRAP, which is an integral membrane protein that localises to GLUT4 storage vesicles that are found in insulin responsive tissues [].
ASAPs (ASAP1, ASAP2, and ASAP3) function as Arf-specific GTPase-activating proteins (GAPs), participate in rhodopsin trafficking, are associated with tumor cell metastasis, modulate phagocytosis, promote cell proliferation, facilitate vesicle budding, Golgi exocytosis, and regulate vesicle coat assembly via a Bin/Amphiphysin/Rvs domain [, , ]. Each member has a BAR, PH, Arf GAP, Ank repeat and proline rich domains. ASAP1 and ASAP2 also have a SH3 domain at the C terminus []. ASAP1 has been implicated in regulating cell motility and invasion []. This entry represents the SH3 domain of ASAP1.
First identified in cyclin-F as a protein-protein interaction motif, the F-boxis a conserved domain that is present in numerous proteins with a bipartite structure []. Through the F-box, these proteins are linked to the Skp1 protein and the core of SCFs (Skp1-cullin-F-box protein ligase) complexes. SCFs complexes constitute a new class of E3 ligases []. They function in combination with the E2 enzyme Cdc34 to ubiquitinate G1 cyclins, Cdk inhibitors and many other proteins, to mark them for degradation. The binding of the specific substrates by SCFs complexes is mediated by divergent protein-protein interaction motifs present in F-box proteins, like WD40 repeats, leucine rich repeats [, ]or ANK repeats.
This entry represents the BAR domain found in ACAP3. BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions [].ACAP3 (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 3) is predicted to be an Arf GTPase activating protein (GAP) based on its similarity to the Arf6-specific GAPs ACAP1 and ACAP2 []. The specific function of ACAP3 is still unknown. ACAP3 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats.
First identified in cyclin-F as a protein-protein interaction motif, the F-boxis a conserved domain that is present in numerous proteins with a bipartite structure []. Through the F-box, these proteins are linked to the Skp1 protein and the core of SCFs (Skp1-cullin-F-box protein ligase) complexes. SCFs complexes constitute a new class of E3 ligases []. They function in combination with the E2 enzyme Cdc34 to ubiquitinate G1 cyclins, Cdk inhibitors and many other proteins, to mark them for degradation. The binding of the specific substrates by SCFs complexes is mediated by divergent protein-protein interaction motifs present in F-box proteins, like WD40 repeats, leucine rich repeats [, ]or ANK repeats.
This entry represents RelA-associated inhibitor (also known as iASPP), which is a regulator that plays acentral role in regulation of apoptosis and transcription via its interaction with NF-kappa-B and p53/TP53 proteins []. iASPP is an ankyrin-repeat-, SH3-domain- and proline-rich-region-containing proteins that is homologous with ASPP1 and ASPP2 (). The ASPPs proteins regulate the apoptotic function of p53; iASPP inhibits p53, whereas ASPP1 and ASPP2 activates p53 []. The p53 tumour suppressor gene is one of the most frequently mutated genes in human cancer that can suppress tumour growth through its ability to induce apoptosis or cell-cycle arrest. Therefore, the ASPP family of proteins may be a novel target for cancer therapy []. This entry also includes ANK repeat-containing protein nipk-1 from the nematode Caenorhabditis elegans, which has been shown to mediate signaling of the receptor complex composed of ilcr-1 and ilcr-2. This complex acts directly on neurons, altering their response properties, modifying behaviour and is the receptor for interleukin-17 [].
ANK-3, also called anykyrin-G (for general or giant), is found in neurons and at least one splice variant has been shown to be essential for propagation of action potentials as a binding partner to neurofascin and voltage-gated sodium channels []. It is required for maintaining axo-dendritic polarity [], and may be a genetic risk factor associated with bipolar disorder []. ANK-3 contains an N-terminal membrane-binding domain containing ANK repeats, a spectrin-binding domain and a C-terminal Death domain. This entry represents the Death domain of ANK-3. DDs (Death domains) are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes [, ].
This domain is present in the N-terminal region of the ShET2 enterotoxin produced by Shigella flexneri () and Escherichia coli (). This protein was found to confer toxigenicity in Ussing chamber assays, and the N-terminal region was found to be important for its enterotoxic effect. The N-terminal domain is a cysteine-type peptidase with a Cys/His/Asp catalytic triad that cleaves within the receptor-interacting protein homotypic interaction motifs found within host adaptor proteins such as receptor-interacting serine/threonine protein kinases RIPK1 and RIPK3, TIR-domain-containing adapter-inducing interferon beta and Z-DNA-binding protein 1, inactivating them and thus inhibiting necroptosis and inflammatory signalling []. The toxin is injected into the host cell by the type III secretion system [].Most proteins containing this domain are annotated as putative enterotoxins, but one member () is a regulator of acetyl CoA synthetase, and another two members (and ) are annotated as ankyrin-like regulatory proteins and contain Ank repeats ().
RelA-associated inhibitor, also known as iASPP, is an oncoprotein that inhibits the apoptotic transactivation potential of p53 [, , ]. It is upregulated in human breast cancers expressing wild-type p53 [], in acute leukemias regardless of the p53 mutation status [], as well as in ovarian cancer where it is associated with poor patient outcome and chemoresistance []. iASPP is also a binding partner and negative regulator of p65RelA, which promotes cell proliferation and inhibits apoptosis; p65RelA has the opposite effect on cell growth compared to the p53 family []. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of iASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53.This entry represents the SH3 domain found in iASPP.
Proteins in this entry contain an N-terminal F-box and a C-terminal F-box associated (FBA) domain. The F-box is a conserved domain that is present in numerous proteins with a bipartite structure []. Through the F-box, these proteins are linked to the Skp1 protein and the core of SCFs (Skp1-cullin-F-box protein ligase) complexes. SCFs complexes constitute a new class of E3 ligases []. They function in combination with the E2 enzyme Cdc34 to ubiquitinate G1 cyclins, Cdk inhibitors and many other proteins, to mark them for degradation. The binding of the specific substrates by SCFs complexes is mediated by divergent protein-protein interaction motifs present in F-box proteins, like WD40 repeats, leucine rich repeats [, ]or ANK repeats.
This entry represents the PH domain of Arf-GAP with SH3 domain, ANK repeat and PH domain-containing proteins (ASAPs). ASAPs (ASAP1, ASAP2, and ASAP3) function as Arf-specific GTPase-activating proteins (GAPs), participate in rhodopsin trafficking, are associated with tumour cell metastasis, modulate phagocytosis, promote cell proliferation, facilitate vesicle budding, Golgi exocytosis, and regulate vesicle coat assembly via a Bin/Amphiphysin/Rvs domain [, , ]. Each member has a BAR, PH, Arf GAP, Ank repeat and proline rich domains. ASAP1 and ASAP2 also have a SH3 domain at the C terminus []. The ASAP family is named for the first identified member, ASAP1 [].PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner []. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity []. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane []. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes [].
This entry represents the N-terminal domain found in a family of neurogenic mastermind-like proteins (MAMLs), which act as critical transcriptional co-activators for Notch signaling [, , ]. Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. MAML proteins may also play roles as key transcriptional co-activators in other signal transduction pathways as well, including: muscle differentiation and myopathies (MEF2C) [], tumour suppressor pathway (p53) []and colon carcinoma survival (beta-catenin) []. MAML proteins could mediate cross-talk among the various signaling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.The N-terminal domain of MAML proteins adopt an elongated kinked helix that wraps around ANK and CSL forming one of the complexes in the build-up of the Notch transcriptional complex for recruiting general transcription factors []. This N-terminal domain is responsible for its interaction with the ankyrin repeat region of the Notch proteins NOTCH1 [], NOTCH2 [], NOTCH3 []and NOTCH4. It forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1, and also binds CREBBP/CBP []and CDK8 []. The C-terminal region is required for transcriptional activation.
This family includes the neurogenic mastermind-like proteins 1-3 (MAML1-3) from chordates, which act as critical transcriptional co-activators for Notch signaling [, ]. Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. MAML proteins may also play roles as key transcriptional co-activators in other signal transduction pathways as well, including: muscle differentiation and myopathies (MEF2C) [], tumour suppressor pathway (p53) []and colon carcinoma survival (beta-catenin) []. MAML proteins could mediate cross-talk among the various signaling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.They consist of an N-terminal domain which adopt an elongated kinked helix that wraps around ANK and CSL forming one of the complexes in the build-up of the Notch transcriptional complex for recruiting general transcription factors [, ]]. This N-terminal domain is responsible for its interaction with the ankyrin repeat region of the Notch proteins NOTCH1 [], NOTCH2 [], NOTCH3 []and NOTCH4. It forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1, and also binds CREBBP/CBP []and CDK8 []. The C-terminal region is required for transcriptional activation.
This entry represents the N-terminal domain found in a family of neurogenic mastermind-like proteins (MAMLs), which act as critical transcriptional co-activators for Notch signaling [, , ]. Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. MAML proteins may also play roles as key transcriptional co-activators in other signal transduction pathways as well, including: muscle differentiation and myopathies (MEF2C) [], tumour suppressor pathway (p53) []and colon carcinoma survival (beta-catenin) []. MAML proteins could mediate cross-talk among the various signaling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.The N-terminal domain of MAML proteins adopt an elongated kinked helix that wraps around ANK and CSL forming one of the complexes in the build-up of the Notch transcriptional complex for recruiting general transcription factors []. This N-terminal domain is responsible for its interaction with the ankyrin repeat region of the Notch proteins NOTCH1 [], NOTCH2 [], NOTCH3 []and NOTCH4. It forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1, and also binds CREBBP/CBP []and CDK8 []. The C-terminal region is required for transcriptional activation.
This domain is found in a group of homeodomain containing proteins from animals, including PHTF1/2, and is typically between 101 and 140 amino acids in length. PHTF proteins do not display any sequence similarity to known or predicted proteins, but their conservation among species suggests an essential function. The 84kDa Phtf1 protein is an integral membrane protein, anchored to a cell membrane by six to eight trans-membrane domains, that is associated with a domain of the endoplasmic reticulum (ER) juxtaposed to the Golgi apparatus. It is present during meiosis and spermiogenesis, and, by the end of spermiogenesis, is released from the mature spermatozoon within the residual bodies []. PHTF1 enhances the binding of FEM1B -feminisation homologue 1B - to cell membranes. Fem-1 was initially identified in the signaling pathway for sex determination, as well as being implicated in apoptosis, but its biochemical role is still unclear, and neither FEM1B nor PHTF1 is directly implicated in apoptosis in spermatogenesis. It is the ANK domain of FEM1B that is necessary for the interaction with the N-terminal region of PHTF1 [].
