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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257      17 LKELINSSENaNKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRdddaFSNVKSLSMDRWTREDIDELVsLGGNKG 96
Cdd:smart00105   1 LKLLRSIPGN-KKCFDCGAPNPTWASVNLGVFLCIECSGIHRSL-GVH----ISKVRSLTLDTWTEEELRLLQ-KGGNEN 73

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*..
gi 6321257      97 NARFWNPKNVPFP--FDGDDDKAIVEHYIRDKYILGKFrYDEIKPED 141
Cdd:smart00105  74 ANSIWESNLDDFSlkPPDDDDQQKYESFIAAKYEEKLF-VPPESAEE 119

GTPase-activating protein (GAP) for the ADP ribosylation factors (ARFs); ArfGAPs are a family of proteins containing an ArfGAP catalytic domain that induces the hydrolysis of GTP bound to the small guanine nucleotide-binding protein Arf, a member of the Ras superfamily of GTPases. Like all GTP-binding proteins, Arf proteins function as molecular switches, cycling between GTP (active-membrane bound) and GDP (inactive-cytosolic) form. Conversion to the GTP-bound form requires a guanine nucleotide exchange factor (GEF), whereas conversion to the GDP-bound form is catalyzed by a GTPase activating protein (GAP). In that sense, ArfGAPs were originally proposed to function as terminators of Arf signaling, which is mediated by regulating Arf family GTP-binding proteins. However, recent studies suggest that ArfGAPs can also function as Arf effectors, independently of their GAP enzymatic activity to transduce signals in cells. The ArfGAP domain contains a C4-type zinc finger motif and a conserved arginine that is required for activity, within a specific spacing (CX2CX16CX2CX4R). ArfGAPs, which have multiple functional domains, regulate the membrane trafficking and actin cytoskeleton remodeling via specific interactions with signaling lipids such as phosphoinositides and trafficking proteins, which consequently affect cellular events such as cell growth, migration, and cancer invasion. The ArfGAP family, which includes 31 human ArfGAP-domain containing proteins, is divided into 10 subfamilies based on domain structure and sequence similarity. The ArfGAP nomenclature is mainly based on the protein domain structure. For example, ASAP1 contains ArfGAP, SH3, ANK repeat and PH domains; ARAPs contain ArfGAP, Rho GAP, ANK repeat and PH domains; ACAPs contain ArfGAP, BAR (coiled coil), ANK repeat and PH domains; and AGAPs contain Arf GAP, GTP-binding protein-like, ANK repeat and PH domains. Furthermore, the ArfGAPs can be classified into two major types of subfamilies, according to the overall domain structure: the ArfGAP1 type includes 6 subfamilies (ArfGAP1, ArfGAP2/3, ADAP, SMAP, AGFG, and GIT), which contain the ArfGAP domain at the N-terminus of the protein; and the AZAP type includes 4 subfamilies (ASAP, ACAP, AGAP, and ARAP), which contain an ArfGAP domain between the PH and ANK repeat domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   17 LKELINSSENaNKCGECGNFYPTWCSVNLGVFLCGRCASVHRKvFGSRdddaFSNVKSLSMDRWTREDIDELVSLGGNKG 96
Cdd:cd08204   1 LEELLKLPGN-KVCADCGAPDPRWASINLGVFICIRCSGIHRS-LGVH----ISKVRSLTLDSWTPEQVELMKAIGNARA 74

                        90       100       110
                ....*....|....*....|....*....|....
gi 6321257   97 NArFWN---PKNVPFPFDGDDDkAIVEHYIRDKY 127
Cdd:cd08204  75 NA-YYEanlPPGFKKPTPDSSD-EEREQFIRAKY 106

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257      17 LKELINSSENaNKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRdddaFSNVKSLSMDRWTREDIDELVsLGGNKG 96
Cdd:smart00105   1 LKLLRSIPGN-KKCFDCGAPNPTWASVNLGVFLCIECSGIHRSL-GVH----ISKVRSLTLDTWTEEELRLLQ-KGGNEN 73

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*..
gi 6321257      97 NARFWNPKNVPFP--FDGDDDKAIVEHYIRDKYILGKFrYDEIKPED 141
Cdd:smart00105  74 ANSIWESNLDDFSlkPPDDDDQQKYESFIAAKYEEKLF-VPPESAEE 119

GTPase-activating protein (GAP) for the ADP ribosylation factors (ARFs); ArfGAPs are a family of proteins containing an ArfGAP catalytic domain that induces the hydrolysis of GTP bound to the small guanine nucleotide-binding protein Arf, a member of the Ras superfamily of GTPases. Like all GTP-binding proteins, Arf proteins function as molecular switches, cycling between GTP (active-membrane bound) and GDP (inactive-cytosolic) form. Conversion to the GTP-bound form requires a guanine nucleotide exchange factor (GEF), whereas conversion to the GDP-bound form is catalyzed by a GTPase activating protein (GAP). In that sense, ArfGAPs were originally proposed to function as terminators of Arf signaling, which is mediated by regulating Arf family GTP-binding proteins. However, recent studies suggest that ArfGAPs can also function as Arf effectors, independently of their GAP enzymatic activity to transduce signals in cells. The ArfGAP domain contains a C4-type zinc finger motif and a conserved arginine that is required for activity, within a specific spacing (CX2CX16CX2CX4R). ArfGAPs, which have multiple functional domains, regulate the membrane trafficking and actin cytoskeleton remodeling via specific interactions with signaling lipids such as phosphoinositides and trafficking proteins, which consequently affect cellular events such as cell growth, migration, and cancer invasion. The ArfGAP family, which includes 31 human ArfGAP-domain containing proteins, is divided into 10 subfamilies based on domain structure and sequence similarity. The ArfGAP nomenclature is mainly based on the protein domain structure. For example, ASAP1 contains ArfGAP, SH3, ANK repeat and PH domains; ARAPs contain ArfGAP, Rho GAP, ANK repeat and PH domains; ACAPs contain ArfGAP, BAR (coiled coil), ANK repeat and PH domains; and AGAPs contain Arf GAP, GTP-binding protein-like, ANK repeat and PH domains. Furthermore, the ArfGAPs can be classified into two major types of subfamilies, according to the overall domain structure: the ArfGAP1 type includes 6 subfamilies (ArfGAP1, ArfGAP2/3, ADAP, SMAP, AGFG, and GIT), which contain the ArfGAP domain at the N-terminus of the protein; and the AZAP type includes 4 subfamilies (ASAP, ACAP, AGAP, and ARAP), which contain an ArfGAP domain between the PH and ANK repeat domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   17 LKELINSSENaNKCGECGNFYPTWCSVNLGVFLCGRCASVHRKvFGSRdddaFSNVKSLSMDRWTREDIDELVSLGGNKG 96
Cdd:cd08204   1 LEELLKLPGN-KVCADCGAPDPRWASINLGVFICIRCSGIHRS-LGVH----ISKVRSLTLDSWTPEQVELMKAIGNARA 74

                        90       100       110
                ....*....|....*....|....*....|....
gi 6321257   97 NArFWN---PKNVPFPFDGDDDkAIVEHYIRDKY 127
Cdd:cd08204  75 NA-YYEanlPPGFKKPTPDSSD-EEREQFIRAKY 106

ArfGAP domain of the AGFG subfamily (ArfGAP domain and FG repeat-containing proteins); The ArfGAP domain and FG repeat-containing proteins (AFGF) subfamily of Arf GTPase-activating proteins consists of the two structurally-related members: AGFG1 and AGFG2. AGFG1 (alias: HIV-1 Rev binding protein, HRB; Rev interacting protein, RIP; Rev/Rex activating domain-binding protein, RAB) and AGFG2 are involved in the maintenance and spread of immunodeficiency virus type 1 (HIV-1) infection. The ArfGAP domain of AGFG is related to nucleoporins, which is a class of proteins that mediate nucleocytoplasmic transport. AGFG plays a role in the Rev export pathway, which mediates the nucleocytoplasmic transfer of proteins and RNAs, possibly together by the nuclear export receptor CRM1. In humans, the presence of the FG repeat motifs (11 in AGFG1 and 7 in AGFG2) are thought to be required for these proteins to act as HIV-1 Rev cofactors. Hence, AGFG promotes movement of Rev-responsive element-containing RNAs from the nuclear periphery to the cytoplasm, which is an essential step for HIV-1 replication.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   14 DRELKELINSSENaNKCGECGNFYPTWCSVNLGVFLCGRCASVHRKvFGSRdddafsnVKSLSMDRWTREDIDELVSlGG 93
Cdd:cd08838   1 EKILRELLKLPEN-KRCFDCGQRGPTYVNLTFGTFVCTTCSGIHRE-FNHR-------VKSISMSTFTPEEVEFLQA-GG 70

                        90       100       110
                ....*....|....*....|....*....|....*....
gi 6321257   94 NKGNARFW----NPKNVPFPFDGDDDKaiVEHYIRDKYI 128
Cdd:cd08838  71 NEVARKIWlakwDPRTDPEPDSGDDQK--IREFIRLKYV 107

Arf1 GTPase-activating protein 1; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   14 DRELKELINSSENaNKCGECGNFYPTWCSVNLGVFLCGRCASVHRkvfgsrdddAF----SNVKSLSMDRWTREDIdELV 89
Cdd:cd08830   2 RAVLRELQKLPGN-NRCFDCGAPNPQWASVSYGIFICLECSGVHR---------GLgvhiSFVRSITMDSWSEKQL-KKM 70

                ....*.
gi 6321257   90 SLGGNK 95
Cdd:cd08830  71 ELGGNA 76

The GIT subfamily of ADP-ribosylation factor GTPase-activating proteins; The GIT (G-protein coupled receptor kinase-interacting protein) subfamily includes GIT1 and GIT2, which have three ANK repeats, a Spa-homology domain (SHD), a coiled-coil domain and a C-terminal paxillin-binding site (PBS). The GIT1/2 proteins are GTPase-activating proteins that function as an inactivator of Arf signaling, and interact with the PIX/Cool family of Rac/Cdc42 guanine nucleotide exchange factors (GEFs). Unlike other ArfGAPs, GIT and PIX (Pak-interacting exchange factor) proteins are tightly associated to form an oligomeric complex that acts as a scaffold and signal integrator that can be recruited for multiple signaling pathways. The GIT/PIX complex functions as a signaling scaffold by binding to specific protein partners. As a result, the complex is transported to specific cellular locations. For instance, the GIT partners paxillin or integrin-alpha4 (to focal adhesions), piccolo and liprin-alpha (to synapses), and the beta-PIX partner Scribble (to epithelial cell-cell contacts and synapses). Moreover, the GIT/PIT complex functions to integrate signals from multiple GTP-binding protein and protein kinase pathways to regulate the actin cytoskeleton and thus cell polarity, adhesion and migration.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   22 NSSENANKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfgSRDddaFSNVKSLSMDRWTREDIdELVSLGGNKGNARFW 101
Cdd:cd08833   3 GKSSNARVCADCSAPDPEWASINRGVLICDECCSIHRSL--GRH---ISQVKSLRKDQWPPSLL-EMVQTLGNNGANSIW 76

                        90       100       110
                ....*....|....*....|....*....|...
gi 6321257  102 -----NPKNVPF--PFDGDDDKAIVEHYIRDKY 127
Cdd:cd08833  77 ehsllDPSQSGKrkPIPPDPVHPTKEEFIKAKY 109

ARF1 GTPase-activating protein 1-like; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   14 DRELKELINSSENaNKCGECGNFYPTWCSVNLGVFLCGRCASVHRKV-----FgsrdddafsnVKSLSMDRWTREDIdEL 88
Cdd:cd08959   2 RAVFKKLRSKPEN-KVCFDCGAKNPQWASVTYGIFICLDCSGVHRGLgvhisF----------VRSTTMDKWTEEQL-RK 69

                        90
                ....*....|.
gi 6321257   89 VSLGGNKgNAR 99
Cdd:cd08959  70 MKVGGNA-NAR 79

Stromal membrane-associated protein 2; a subfamily of the ArfGAP family; The SMAP subfamily of Arf GTPase-activating proteins consists of the two structurally-related members, SMAP1 and SMAP2. Each SMAP member exhibits common and distinct functions in vesicle trafficking. They both bind to clathrin heavy chain molecules and are involved in the trafficking of clathrin-coated vesicles. SMAP1 preferentially exhibits GAP toward Arf6, while SMAP2 prefers Arf1 as a substrate. SMAP1 is involved in Arf6-dependent vesicle trafficking, but not Arf6-mediated actin cytoskeleton reorganization, and regulates clathrin-dependent endocytosis of the transferrin receptors and E-cadherin. SMAP2 regulates Arf1-dependent retrograde transport of TGN38/46 from the early endosome to the trans-Golgi network (TGN). SMAP2 has the Clathrin Assembly Lymphoid Myeloid (CALM)-binding domain, but SMAP1 does not.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   17 LKELINSSENaNKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRdddaFSNVKSLSMDRWTREDIDELVSLGGNKG 96
Cdd:cd08859   1 LASLLLEEEN-KFCADCQSKGPRWASWNIGVFICIRCAGIHRNL-GVH----ISRVKSVNLDQWTQEQIQCMQEMGNGKA 74

                        90       100       110
                ....*....|....*....|....*....|...
gi 6321257   97 NARF--WNPKNVPFPfdgDDDKAiVEHYIRDKY 127
Cdd:cd08859  75 NRLYeaFLPENFRRP---QTDQA-VEGFIRDKY 103

UBA domain of eukaryotic protein linking integrin-associated protein with cytoskeleton (PLIC) proteins, Saccharomyces cerevisiae proteins Dsk2p and Gts1p, and similar proteins; The PLIC proteins (or ubiquilins) family contains human homologs of the yeast ubiquitin-like Dsk2 protein, PLIC-1 (also called ubiquilin-1), PLIC-2 (also called ubiquilin-2 or Chap1), PLIC-3 (also called ubiquilin-3) and PLIC-4 (also called ubiquilin-4, Ataxin-1 interacting ubiquitin-like protein, A1Up, Connexin43-interacting protein of 75 kDa, or CIP75), and mouse PLIC proteins. They are ubiquitin-binding adaptor proteins involved in all protein degradation pathways through delivering ubiquitinated substrates to proteasomes. They also promote autophagy-dependent cell survival during nutrient starvation. Saccharomyces cerevisiae Dsk2p is a nuclear-enriched protein that may involve in the ubiquitin-proteasome proteolytic pathway through interacting with K48-linked polyubiquitin and the proteasome. Gts1p, also called protein LSR1, is encoded by a pleiotropic gene GTS1 in budding yeast. The formation of Gts1p-mediated protein aggregates may induce reactive oxygen species (ROS) production and apoptosis. Gts1p also plays an important role in the regulation of heat and other stress responses under glucose-limited or -depleted conditions in either batch or continuous culture.

                        10        20        30
                ....*....|....*....|....*....|....*....
gi 6321257  194 RYSRQLAELKDMGFGDTNKNLDALSSAHGNINRAIDYLE 232
Cdd:cd14323   1 RYQQQLATLKEMGFNDTEKNLQALSATGGNINLAIERLF 39

ArfGAP domain of ACAP (ArfGAP with Coiled-coil, ANK repeat and PH domains) proteins; ArfGAP domain is an essential part of ACAP proteins that play important role in endocytosis, actin remodeling and receptor tyrosine kinase-dependent cell movement. ACAP subfamily of ArfGAPs are composed of coiled coils (BAR, Bin-Amphiphysin-Rvs), PH, ArfGAP and ANK repeats domains. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) have a GAP (GTPase-activating protein) activity preferentially toward Arf6, which regulates endocytic recycling. Both ACAP1/2 are activated by are activated by the phosphoinositides, PI(4,5)P2 and PI(3,5)P2. ACAP1 binds specifically with recycling cargo proteins such as transferrin receptor (TfR) and cellubrevin. Thus, ACAP1 promotes cargo sorting to enhance TfR recycling from the recycling endosome. In addition, phosphorylation of ACAP by Akt, a serine/threonine protein kinase, regulates the recycling of integrin beta1 to control cell migration. In contrast, ACAP2 does not exhibit a similar interaction with the recycling cargo proteins. It has been shown that ACAP2 functions both as an effector of Ras-related protein Rab35 and as an Arf6-GTPase-activating protein (GAP) during neurite outgrowth of PC12 cells. In addition, ACAP2, together with Rab35, regulates phagocytosis in mammalian macrophages. ACAP3 also positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   28 NKCGECGNFYPTWCSVNLGVFLCGRCASVHRKvFGSRdddaFSNVKSLSMDRWTREDIDELVSLGGNKGNARFWNpkNVP 107
Cdd:cd08835  14 AQCCDCGSPDPRWASINLGVTLCIECSGIHRS-LGVH----VSKVRSLTLDSWEPELLKVMLELGNDVVNRIYEA--NVP 86

                        90       100       110
                ....*....|....*....|....*....|..
gi 6321257  108 fpfDGDDDKA-------IVEHYIRDKYILGKF 132
Cdd:cd08835  87 ---DDGSVKPtpdssrqEREAWIRAKYVEKKF 115

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 2; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics. ARAP2 localizes to the cell periphery and on focal adhesions composed of paxillin and vinculin, and functions downstream of RhoA to regulate focal adhesion dynamics. ARAP2 is a PI(3,4,5)P3-dependent Arf6 GAP that binds RhoA-GTP, but it lacks the predicted catalytic arginine in the RhoGAP domain and does not have RhoGAP activity. ARAP2 reduces Rac1oGTP levels by reducing Arf6oGTP levels through GAP activity. AGAP2 also binds to and regulates focal adhesion kinase (FAK). Thus, ARAP2 signals through Arf6 and Rac1 to control focal adhesion morphology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   14 DRELKELINSSENANKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRDddafSNVKSLSMDR--WTREDIdELVSL 91
Cdd:cd08856   5 DYEVAEKIWFNESNRSCADCKAPDPDWASINLCVVICKKCAGQHRSL-GPKD----SKVRSLKMDAsiWSNELI-ELFIV 78

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 6321257   92 GGNKGNARFWN---PKNVPFPFDGDDDKAivEHYIRDKYILGKFR 133
Cdd:cd08856  79 VGNKPANLFWAanlFSEEDLHMDSDVEQR--TPFITQKYKEGKFR 121

ArfGAP with GTPase domain, ANK repeat and PH domains; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   28 NKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRdddaFSNVKSLSMDRWTREDIDELVSLGGNKGNaRFW----NP 103
Cdd:cd08836  13 DHCVDCGAPNPDWASLNLGALMCIECSGIHRNL-GTH----ISRVRSLDLDDWPVELLKVMSAIGNDLAN-SVWegntQG 86

                        90       100
                ....*....|....*....|....
gi 6321257  104 KNVPFPFDGDDDKaivEHYIRDKY 127
Cdd:cd08836  87 RTKPTPDSSREEK---ERWIRAKY 107

ArfGAP domain of ACAP2 (ArfGAP with Coiled-coil, ANK repeat and PH domains 2); ACAP2 belongs to the ACAP subfamily of GAPs (GTPase-activating proteins) for the small GTPase Arf (ADP-ribosylation factor). ACAP subfamily of ArfGAPs are composed of Coiled coli (BAR, Bin-Amphiphysin-Rvs), PH, ArfGAP and ANK repeats domains. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) have a GAP (GTPase-activating protein) activity preferentially toward Arf6, which regulates endocytic recycling. Both ACAP1/2 are activated by are activated by the phosphoinositides, PI(4,5)P2 and PI(3,5)P2. ACAP1 binds specifically with recycling cargo proteins such as transferrin receptor (TfR) and cellubrevin. Thus, ACAP1 promotes cargo sorting to enhance TfR recycling from the recycling endosome. In addition, phosphorylation of ACAP by Akt, a serine/threonine protein kinase, regulates the recycling of integrin beta1 to control cell migration. In contrast, ACAP2 does not exhibit a similar interaction with the recycling cargo proteins. It has been shown that ACAP2 functions both as an effector of Ras-related protein Rab35 and as an Arf6-GTPase-activating protein (GAP) during neurite outgrowth of PC12 cells. Moreover, ACAP2, together with Rab35, regulates phagocytosis in mammalian macrophages. ACAP3 also positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   26 NANkCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRdddaFSNVKSLSMDRWTREDIDELVSLGGNKGNaRFWNPK- 104
Cdd:cd08851  13 NAS-CCDCGLADPRWASINLGITLCIECSGIHRSL-GVH----FSKVRSLTLDTWEPELLKLMCELGNDVIN-RIYEARv 85

                        90       100       110
                ....*....|....*....|....*....|.
gi 6321257  105 ---NVPFPFDGDDDKAIvEHYIRDKYILGKF 132
Cdd:cd08851  86 ekmGAKKPQPGGQRQEK-EAYIRAKYVERKF 115

ArfGAP domain of ASAP (Arf GAP, SH3, ANK repeat and PH domains) subfamily of ADP-ribosylation factor GTPase-activating proteins; The ArfGAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP3, ASAP1 and ASAP2 also have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport. ASAP3 is a focal adhesion-associated ArfGAP that functions in cell migration and invasion. Similar to ASAP1, the GAP activity of ASAP3 is strongly enhanced by PIP2 via PH domain. Like ASAP1, ASAP3 associates with focal adhesions and circular dorsal ruffles. However, unlike ASAP1, ASAP3 does not localize to invadopodia or podosomes. Both ASAP 1 and 3 have been implicated in oncogenesis, as ASAP1 is highly expressed in metastatic breast cancer and ASAP3 in hepatocellular carcinoma.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   28 NKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRdddaFSNVKSLSMDRWTREDIDELVSLGGNKGNARF---WNPK 104
Cdd:cd08834  16 DVCCDCGSPDPTWLSTNLGILTCIECSGVHREL-GVH----VSRIQSLTLDNLGTSELLLARNLGNEGFNEIMeanLPPG 90

                        90       100
                ....*....|....*....|....*...
gi 6321257  105 NVPFPFDGDDDKAiveHYIRDKYILGKF 132
Cdd:cd08834  91 YKPTPNSDMEERK---DFIRAKYVEKKF 115

ArfGAP with GTPase domain, ANK repeat and PH domain 1; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   21 INSSENANKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRdddaFSNVKSLSMDRWTREDIDELVSLGGNKGNaRF 100
Cdd:cd08854   7 IRNAKGNSLCVDCGAPNPTWASLNLGALICIECSGIHRNL-GTH----LSRVRSLDLDDWPRELTLVLTAIGNHMAN-SI 80

                        90       100       110
                ....*....|....*....|....*....|.
gi 6321257  101 WNP----KNVPFPFDGDDDKaivEHYIRDKY 127
Cdd:cd08854  81 WESctqgRTKPAPDSSREER---ESWIRAKY 108

ArfGAP domain of ASAP3 (ArfGAP with ANK repeat and PH domain-containing protein 3); The ArfGAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP1 and ASAP2, ASAP3 do not have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport. ASAP3 is a focal adhesion-associated ArfGAP that functions in cell migration and invasion. Similar to ASAP1, the GAP activity of ASAP3 is strongly enhanced by PIP2 via PH domain. Like ASAP1, ASAP3 associates with focal adhesions and circular dorsal ruffles. However, unlike ASAP1, ASAP3 does not localize to invadopodia or podosomes. ASAP 1 and 3 have been implicated in oncogenesis, as ASAP1 is highly expressed in metastatic breast cancer and ASAP3 in hepatocellular carcinoma.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   18 KELINSSEN--ANK-CGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRdddaFSNVKSLSMDRWTredIDELVsLGGN 94
Cdd:cd17900   3 KLLIAEVKSrpGNSqCCDCGAPDPTWLSTNLGILTCIECSGIHREL-GVR----YSRIQSLTLDLLS---TSELL-LAVS 73

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 6321257   95 KGNARF-----------WNPKNVPfpfdgDDDKAIVEHYIRDKYILGKF 132
Cdd:cd17900  74 MGNTRFnevmeatlpahGGPKPSA-----ESDMGTRKDYIMAKYVEHRF 117

UBA domain of Saccharomyces cerevisiae proteasome interacting protein Dsk2p and its homologs found in fungi; The family contains several fungal multi-ubiquitin receptors, including Saccharomyces cerevisiae Dsk2p and Schizosaccharomyces pombe Dph1p, both of which have been characterized as shuttle proteins transporting ubiquitinated substrates destined for degradation from the E3 ligase to the 26S proteasome. They interact with the proteasome through their N-terminal ubiquitin-like domain (UBL) and with ubiquitin (Ub) through their C-terminal ubiquitin-associated domain (UBA). S. cerevisiae Dsk2p is a nuclear-enriched protein that may involve in the ubiquitin-proteasome proteolytic pathway through interacting with K48-linked polyubiquitin and the proteasome. Moreover, it has been implicated in spindle pole duplication through assisting in Cdc31 assembly into the new spindle pole body (SPB). S. pombe Dph1p is a ubiquitin receptor working in concert with the class V myosin, Myo52, to target the degradation of the S. pombe CLIP-170 homolog, Tip1. It also can protect ubiquitin chains against disassembly by deubiquitinating enzymes.

                        10        20        30
                ....*....|....*....|....*....|....*...
gi 6321257  194 RYSRQLAELKDMGFGDTNKNLDALSSAHGNINRAIDYL 231
Cdd:cd14324   4 RYEEQLRQLNEMGFFDFDRNVRALRRSGGSVQGAVESL 41

ArfGAP with GTPase domain, ANK repeat and PH domain 3; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   30 CGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRdddaFSNVKSLSMDRWTREDIDELVSLGGNKGNArFW----NPKN 105
Cdd:cd08855  17 CIDCDAPNPDWASLNLGALMCIECSGIHRNL-GTH----LSRVRSLDLDDWPVELSMVMTAIGNAMANS-VWegalDGYS 90

                        90       100
                ....*....|....*....|..
gi 6321257  106 VPFPFDGDDDKaivEHYIRDKY 127
Cdd:cd08855  91 KPGPDSTREEK---ERWIRAKY 109

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257    17 LKELINSSENaNKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfgsrdDDAFSNVKSLSMDRWTREDIDELVSLGGNKG 96
Cdd:PLN03114  13 FKKLKAKSDN-KICFDCNAKNPTWASVTYGIFLCIDCSAVHRSL-----GVHISFVRSTNLDSWSSEQLKMMIYGGNNRA 86

                 ....
gi 6321257    97 NARF 100
Cdd:PLN03114  87 QVFF 90

ArfGAP domain of ASAP2 (ArfGAP2 with SH3 domain, ANK repeat and PH domain-containing protein 2); The Arf GAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf , thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP3, ASAP1 and ASAP2 also have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   30 CGECGNFYPTWCSVNLGVFLCGRCASVHRKVfGSRdddaFSNVKSLSMDRWTredIDELVsLGGNKGNARFWN------P 103
Cdd:cd08849  18 CCDCGAPDPTWLSTNLGILTCIECSGIHREL-GVH----YSRMQSLTLDVLG---TSELL-LAKNIGNAGFNEimeaclP 88

                        90       100
                ....*....|....*....|....*....
gi 6321257  104 KNVPFPFDGDDDKAIVEHYIRDKYILGKF 132
Cdd:cd08849  89 AEDVVKPNPGSDMNARKDYITAKYIERRY 117

ArfGAP domain of AGFG2 (ArfGAP domain and FG repeat-containing protein 2); The ArfGAP domain and FG repeat-containing proteins (AFGF) subfamily of Arf GTPase-activating proteins consists of the two structurally-related members: AGFG1 and AGFG2. AGFG2 is a member of the HIV-1 Rev binding protein (HRB) family and contains one Arf-GAP zinc finger domain, several Phe-Gly (FG) motifs, and four Asn-Pro-Phe (NPF) motifs. AGFG2 interacts with Eps15 homology (EH) domains and plays a role in the Rev export pathway, which mediates the nucleocytoplasmic transfer of proteins and RNAs. In humans, the presence of the FG repeat motifs (11 in AGFG1 and 7 in AGFG2) are thought to be required for these proteins to act as HIV-1 Rev cofactors. Hence, AGFG promotes movement of Rev-responsive element-containing RNAs from the nuclear periphery to the cytoplasm, which is an essential step for HIV-1 replication.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   15 RELKELINSSENANKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfgsrddDAFSNVKSLSMDRWTREDIdELVSLGGN 94
Cdd:cd17903   2 RRVRELGGCSAANRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGL------NPPHRVKSISMTTFTEPEV-LFLQARGN 74

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 6321257   95 KGNARFW----NPKNVPFPFDGDDDKaiVEHYIRDKY 127
Cdd:cd17903  75 EVCRKIWlglfDARTSLIPDSRDPQK--VKEFLQEKY 109

ArfGAP domain of AGFG1 (ArfGAP domain and FG repeat-containing protein 1); The ArfGAP domain and FG repeat-containing proteins (AFGF) subfamily of Arf GTPase-activating proteins consists of the two structurally-related members: AGFG1 and AGFG2. AGFG1 (alias: HIV-1 Rev binding protein, HRB; Rev interacting protein, RIP; Rev/Rex activating domain-binding protein, RAB) and AGFG2 are involved in the maintenance and spread of immunodeficiency virus type 1 (HIV-1) infection. The ArfGAP domain of AGFG1 is related to nucleoporins, which is a class of proteins that mediate nucleocytoplasmic transport. AGFG1 plays a role in the Rev export pathway, which mediates the nucleocytoplasmic transfer of proteins and RNAs, possibly together by the nuclear export receptor CRM1. In humans, the presence of the FG repeat motifs (11 in AGFG1 and 7 in AGFG2) are thought to be required for these proteins to act as HIV-1 Rev cofactors. Hence, AGFG1 promotes movement of Rev-responsive element-containing RNAs from the nuclear periphery to the cytoplasm, which is an essential step for HIV-1 replication.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6321257   17 LKELINSSENaNKCGECGNFYPTWCSVNLGVFLCGRCASVHRKVfgsrddDAFSNVKSLSMDRWTREDIdELVSLGGNKG 96
Cdd:cd08857   5 LREMTSLPHN-RKCFDCDQRGPTYANMTVGSFVCTSCSGILRGL------NPPHRVKSISMTTFTQQEI-EFLQKHGNEV 76

                        90       100       110
                ....*....|....*....|....*....|....*
gi 6321257   97 NARFW----NPKNVPFPFDGDDDKaiVEHYIRDKY 127
Cdd:cd08857  77 CKQIWlglfDDRSSAIPDFRDPQK--VKEFLQEKY 109