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 79494602   8 EKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREFTHRVKSVSMAKFTADEVSALRAGGNERARQIYFK 87
Cdd:cd08838   1 EKILRELLKLPENKRCFDCGQRGPTYVNLTFGTFVCTTCSGIHREFNHRVKSISMSTFTPEEVEFLQAGGNEVARKIWLA 80

                        90       100       110
                ....*....|....*....|....*....|...
gi 79494602  88 EWDAHRDGYPDRSNIFKLRDFIRSVYVDKRYSS 120
Cdd:cd08838  81 KWDPRTDPEPDSGDDQKIREFIRLKYVDKRWYD 113

BDLF3; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602  285 VPVSELSDEGIIKNSSeipASLKTTEEP-------APNSLEALLFGSSVPSVvPGTNNYELWNTSDISSTENYTAVNLGT 357
Cdd:PHA03255  43 VTTPSPSASGPSTNQS---TTLTTTSAPitttailSTNTTTVTSTGTTVTPV-PTTSNASTINVTTKVTAQNITATEAGT 118

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 79494602  358 QTMPGIPDSVTSFATSPTTAHAHSGSSGPVVPVAPDNLNTKETATLANNQGPSD 411
Cdd:PHA03255 119 GTSTGVTSNVTTRSSSTTSATTRITNATTLAPTLSSKGTSNATKTTAELPTVPD 172

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 79494602   8 EKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREFTHRVKSVSMAKFTADEVSALRAGGNERARQIYFK 87
Cdd:cd08838   1 EKILRELLKLPENKRCFDCGQRGPTYVNLTFGTFVCTTCSGIHREFNHRVKSISMSTFTPEEVEFLQAGGNEVARKIWLA 80

                        90       100       110
                ....*....|....*....|....*....|...
gi 79494602  88 EWDAHRDGYPDRSNIFKLRDFIRSVYVDKRYSS 120
Cdd:cd08838  81 KWDPRTDPEPDSGDDQKIREFIRLKYVDKRWYD 113

putative ADP-ribosylation factor GTPase-activating protein AGD14; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602    2 KEDERTEKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREFTHRVKSVSMAKFTADEVSALRAGGNERA 81
Cdd:PLN03119   5 REEERNEKIIRGLMKLPPNRRCINCNSLGPQYVCTTFWTFVCMACSGIHREFTHRVKSVSMSKFTSKEVEVLQNGGNQRA 84

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602   82 RQIYFKEWDAHRDGYPDRSNIFKLRDFIRSVYVDKRYSSSDKISQQKSDvTEDYRESKKTSAHvlgSRSLHSVDKS-DIE 160
Cdd:PLN03119  85 REIYLKNWDHQRQRLPENSNAERVREFIKNVYVQKKYAGANDADKPSKD-SQDHVSSEDMTRR---ANSYHSYSQSpPYD 160

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602  161 RSSAAGRSGSESLRFYFDDKNHKQQHVthnpRSRGLPKSPIRF--EIVDDRFRDDGSVKR 218
Cdd:PLN03119 161 YQYEERRYGKIPLGFTGKSASVKGLHA----KASSFVYSPGRFsdHMFEDQFSNEDSAPR 216

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 79494602     11 IRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHRE-FTHR--VKSVSMAKFTADEVSALRAGGNERARQIyfk 87
Cdd:smart00105   1 LKLLRSIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSlGVHIskVRSLTLDTWTEEELRLLQKGGNENANSI--- 77

                           90       100       110
                   ....*....|....*....|....*....|....
gi 79494602     88 eWDAH---RDGYPDRSNIFKLRD-FIRSVYVDKR 117
Cdd:smart00105  78 -WESNlddFSLKPPDDDDQQKYEsFIAAKYEEKL 110

BDLF3; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602  285 VPVSELSDEGIIKNSSeipASLKTTEEP-------APNSLEALLFGSSVPSVvPGTNNYELWNTSDISSTENYTAVNLGT 357
Cdd:PHA03255  43 VTTPSPSASGPSTNQS---TTLTTTSAPitttailSTNTTTVTSTGTTVTPV-PTTSNASTINVTTKVTAQNITATEAGT 118

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 79494602  358 QTMPGIPDSVTSFATSPTTAHAHSGSSGPVVPVAPDNLNTKETATLANNQGPSD 411
Cdd:PHA03255 119 GTSTGVTSNVTTRSSSTTSATTRITNATTLAPTLSSKGTSNATKTTAELPTVPD 172

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 79494602   8 EKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREFTHRVKSVSMAKFTADEVSALRAGGNERARQIYFK 87
Cdd:cd08838   1 EKILRELLKLPENKRCFDCGQRGPTYVNLTFGTFVCTTCSGIHREFNHRVKSISMSTFTPEEVEFLQAGGNEVARKIWLA 80

                        90       100       110
                ....*....|....*....|....*....|...
gi 79494602  88 EWDAHRDGYPDRSNIFKLRDFIRSVYVDKRYSS 120
Cdd:cd08838  81 KWDPRTDPEPDSGDDQKIREFIRLKYVDKRWYD 113

putative ADP-ribosylation factor GTPase-activating protein AGD14; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602    2 KEDERTEKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREFTHRVKSVSMAKFTADEVSALRAGGNERA 81
Cdd:PLN03119   5 REEERNEKIIRGLMKLPPNRRCINCNSLGPQYVCTTFWTFVCMACSGIHREFTHRVKSVSMSKFTSKEVEVLQNGGNQRA 84

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602   82 RQIYFKEWDAHRDGYPDRSNIFKLRDFIRSVYVDKRYSSSDKISQQKSDvTEDYRESKKTSAHvlgSRSLHSVDKS-DIE 160
Cdd:PLN03119  85 REIYLKNWDHQRQRLPENSNAERVREFIKNVYVQKKYAGANDADKPSKD-SQDHVSSEDMTRR---ANSYHSYSQSpPYD 160

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602  161 RSSAAGRSGSESLRFYFDDKNHKQQHVthnpRSRGLPKSPIRF--EIVDDRFRDDGSVKR 218
Cdd:PLN03119 161 YQYEERRYGKIPLGFTGKSASVKGLHA----KASSFVYSPGRFsdHMFEDQFSNEDSAPR 216

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 79494602   9 KAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREFT--HRVKSVSMAKFTADEVSALRAGGNERARQIYF 86
Cdd:cd08857   3 KMLREMTSLPHNRKCFDCDQRGPTYANMTVGSFVCTSCSGILRGLNppHRVKSISMTTFTQQEIEFLQKHGNEVCKQIWL 82

                        90       100       110
                ....*....|....*....|....*....|..
gi 79494602  87 KEWDAHRDGYPDRSNIFKLRDFIRSVYVDKRY 118
Cdd:cd08857  83 GLFDDRSSAIPDFRDPQKVKEFLQEKYEKKRW 114

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 79494602  11 IRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF-TH--RVKSVSMAKFTADEVSALRAGGNERARQIyfk 87
Cdd:cd08204   1 LEELLKLPGNKVCADCGAPDPRWASINLGVFICIRCSGIHRSLgVHisKVRSLTLDSWTPEQVELMKAIGNARANAY--- 77

                        90       100       110
                ....*....|....*....|....*....|
gi 79494602  88 eWDAHRDGYPDR----SNIFKLRDFIRSVY 113
Cdd:cd08204  78 -YEANLPPGFKKptpdSSDEEREQFIRAKY 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 79494602     11 IRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHRE-FTHR--VKSVSMAKFTADEVSALRAGGNERARQIyfk 87
Cdd:smart00105   1 LKLLRSIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSlGVHIskVRSLTLDTWTEEELRLLQKGGNENANSI--- 77

                           90       100       110
                   ....*....|....*....|....*....|....
gi 79494602     88 eWDAH---RDGYPDRSNIFKLRD-FIRSVYVDKR 117
Cdd:smart00105  78 -WESNlddFSLKPPDDDDQQKYEsFIAAKYEEKL 110

Arf1 GTPase-activating protein 2/3-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 79494602  12 RSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF-TH--RVKSVSMAKFTADEVSALRAGGNERARQiYFKE 88
Cdd:cd08831   7 KKLRSKPENKVCFDCGAKNPTWASVTFGVFLCLDCSGVHRSLgVHisFVRSTNLDSWTPEQLRRMKVGGNAKARE-FFKQ 85

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 79494602   7 TEKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF-TH--RVKSVSMAKFTADEVSALRAGGNERARQ 83
Cdd:cd08834   2 TKSIIAEVKRLPGNDVCCDCGSPDPTWLSTNLGILTCIECSGVHRELgVHvsRIQSLTLDNLGTSELLLARNLGNEGFNE 81

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 79494602  84 IYfkEWDAHRDGYPD-RSNIFKLRDFIRSVYVDKRY 118
Cdd:cd08834  82 IM--EANLPPGYKPTpNSDMEERKDFIRAKYVEKKF 115

GTPase-activating protein that regulates ARFs (ADP-ribosylation factors), involved in ARF-mediated vesicular transport [Intracellular trafficking and secretion];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602   1 MKEDERTEKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHRE-FTH--RVKSVSMAKFTADEVSALRAGG 77
Cdd:COG5347   1 MSTKSEDRKLLKLLKSDSSNKKCADCGAPNPTWASVNLGVFLCIDCAGVHRSlGVHisKVKSLTLDNWTEEELRRMEVGG 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602  78 NERARQIyfkeWDAHrdgyPDRSNIFKLR---------DFIRSVYVDKR-------YSSSDKISQQKS-------DVTED 134
Cdd:COG5347  81 NSNANRF----YEKN----LLDQLLLPIKakydssvakKYIRKKYELKKfiddsssPSDFSSFSASSTrtvdsvdDRLDS 152

                       170       180       190       200
                ....*....|....*....|....*....|....*....|
gi 79494602 135 YRESKKTSAHVLGSrslhsvDKSDIERSSAAGRSGSESLR 174
Cdd:COG5347 153 ESQSRSSSASLGNS------NRPDDELNVESFQSTGSKPR 186

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 79494602  13 SLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF-TH--RVKSVSMAKFTADEVSALRAGGNERARQIY 85
Cdd:cd08859   3 SLLLEEENKFCADCQSKGPRWASWNIGVFICIRCAGIHRNLgVHisRVKSVNLDQWTQEQIQCMQEMGNGKANRLY 78

ArfGAP domain of ASAP1 (ArfGAP with SH3 domain, ANK repeat and PH domain-containing protein 1); 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. 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 79494602   7 TEKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF---THRVKSVSMAKFTADEVSALRAGGNERARQ 83
Cdd:cd08848   2 TKAIIDDVQRLPGNEVCCDCGSPDPTWLSTNLGILTCIECSGIHREMgvhISRIQSLELDKLGTSELLLAKNVGNNSFND 81

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 79494602  84 IYFKEWDAHRDGYPDRSNIFKLRDFIRSVYVDKRYS 119
Cdd:cd08848  82 IMEGNLPSPSPKPSPSSDMTARKEYITAKYVEHRFS 117

ArfGAP with GTPase domain, ANK repeat and PH domain 2; 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 79494602  10 AIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF-TH--RVKSVSMAKFTADEVSALRAGGNERARQIYF 86
Cdd:cd08853   3 ALQSIRNMRGNSHCVDCETQNPKWASLNLGVLMCIECSGIHRNLgTHlsRVRSLDLDDWPVELRKVMSSIGNELANSIWE 82

                        90       100
                ....*....|....*....|....*..
gi 79494602  87 KEWDAHRDGYPDRSNIFKLRdFIRSVY 113
Cdd:cd08853  83 GSSQGQTKPSSDSTREEKER-WIRAKY 108

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 79494602  10 AIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF-TH--RVKSVSMAKFTADEVSALRAGGNERARQIyf 86
Cdd:cd08855   4 AIQSIRNVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRNLgTHlsRVRSLDLDDWPVELSMVMTAIGNAMANSV-- 81

                        90       100       110
                ....*....|....*....|....*....|.
gi 79494602  87 keWDAHRDGY----PDRSNIFKLRdFIRSVY 113
Cdd:cd08855  82 --WEGALDGYskpgPDSTREEKER-WIRAKY 109

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 79494602   7 TEKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF-TH--RVKSVSMAKFTADEVSALRAGGNERARQ 83
Cdd:cd08849   2 TKEIISEVQRMTGNDVCCDCGAPDPTWLSTNLGILTCIECSGIHRELgVHysRMQSLTLDVLGTSELLLAKNIGNAGFNE 81

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 79494602  84 IYFKEWDAHRDGYPD-RSNIFKLRDFIRSVYVDKRYS 119
Cdd:cd08849  82 IMEACLPAEDVVKPNpGSDMNARKDYITAKYIERRYA 118

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 79494602  10 AIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF-TH--RVKSVSMAKFTADEVSALRAGGNERARQIYf 86
Cdd:cd08854   3 AIQAIRNAKGNSLCVDCGAPNPTWASLNLGALICIECSGIHRNLgTHlsRVRSLDLDDWPRELTLVLTAIGNHMANSIW- 81

                        90       100
                ....*....|....*....|....*...
gi 79494602  87 kEWDAHRDGYPDRSNIFKLRD-FIRSVY 113
Cdd:cd08854  82 -ESCTQGRTKPAPDSSREEREsWIRAKY 108

Arf1 GTPase-activating protein 3; 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 79494602  12 RSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREFTHRVKSVSMAKFTAD----EVSALRAGGNERArQIYFK 87
Cdd:cd09028  11 KRLRSVPTNKVCFDCGAKNPSWASITYGVFLCIDCSGIHRSLGVHLSFIRSTELDSNwswfQLRCMQVGGNANA-SAFFH 89

                .
gi 79494602  88 E 88
Cdd:cd09028  90 Q 90

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 79494602   8 EKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF-TH--RVKSVSMAKFTADEVSALRAGGNERARQI 84
Cdd:cd08851   1 ESALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLgVHfsKVRSLTLDTWEPELLKLMCELGNDVINRI 80

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 79494602  85 Y---FKEWDAHRDGYPDRSNifKLRDFIRSVYVDKRY 118
Cdd:cd08851  81 YearVEKMGAKKPQPGGQRQ--EKEAYIRAKYVERKF 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 79494602  20 NRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF---THRVKSVSM-AKFTADE-VSALRAGGNERARQIY----FKEWD 90
Cdd:cd08856  18 NRSCADCKAPDPDWASINLCVVICKKCAGQHRSLgpkDSKVRSLKMdASIWSNElIELFIVVGNKPANLFWaanlFSEED 97

                        90       100
                ....*....|....*....|....*...
gi 79494602  91 AHRDGYPDRSnifklRDFIRSVYVDKRY 118
Cdd:cd08856  98 LHMDSDVEQR-----TPFITQKYKEGKF 120

ArfGAP domain of ACAP3 (ArfGAP with Coiled-coil, ANK repeat and PH domains 3); ACAP3 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. It has been shown that ACAP3 positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) also 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79494602   8 EKAIRSLLKLPENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF-TH--RVKSVSMAKFTADEVSALRAGGNERARQI 84
Cdd:cd08850   1 ESILQRVQSIAGNDQCCDCGQPDPRWASINLGILLCIECSGIHRSLgVHcsKVRSLTLDSWEPELLKLMCELGNSTVNQI 80

                        90       100       110
                ....*....|....*....|....*....|....*
gi 79494602  85 YFKEWDAHRDGYPDRSNIFKLRD-FIRSVYVDKRY 118
Cdd:cd08850  81 YEAQCEELGLKKPTASSSRQDKEaWIKAKYVEKKF 115

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 1; 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. ARAP1 localizes to the plasma membrane, the Golgi complex, and endosomal compartments. It displays PI(3,4,5)P3-dependent ArfGAP activity that regulates Arf-, RhoA-, and Cdc42-dependent cellular events. For example, ARAP1 inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 79494602  18 PENRRCINCNSLGPQYVCSTFWTFVCVNCSGIHREF---THRVKSVSMAK--FTADEVSALRAGGNERARQIY 85
Cdd:cd17901  11 ESNRFCADCGSPKPDWASVNLCVVICKRCAGEHRGLgpsVSKVRSLKMDRkvWTEELIELFLLLGNGKANQFW 83