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 1002256249  14 ERVVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREFTHRVKSVSMSTFTTQEVEALQNGGNQRARESFLK 93
Cdd:cd08838     1 EKILRELLKLPENKRCFDCGQRGPTYVNLTFGTFVCTTCSGIHREFNHRVKSISMSTFTPEEVEFLQAGGNEVARKIWLA 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1002256249  94 EFDAQKMRLPDSSNVDSLREFIKAVYVERRY 124
Cdd:cd08838    81 KWDPRTDPEPDSGDDQKIREFIRLKYVDKRW 111

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 1002256249   20 LLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHRE-FTHR--VKSVSMSTFTTQEVEALQNGGNQRARESFLKEFD 96
Cdd:smart00105   4 LRSIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSlGVHIskVRSLTLDTWTEEELRLLQKGGNENANSIWESNLD 83

                           90       100
                   ....*....|....*....|....*..
gi 1002256249   97 AQKMRLPDSSNVDSLREFIKAVYVERR 123
Cdd:smart00105  84 DFSLKPPDDDDQQKYESFIAAKYEEKL 110

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002256249   5 ASRKEEERNERVVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREFTHRVKSVSMSTFTTQEVEALQNGGN 84
Cdd:PLN03119    2 GSKREEERNEKIIRGLMKLPPNRRCINCNSLGPQYVCTTFWTFVCMACSGIHREFTHRVKSVSMSKFTSKEVEVLQNGGN 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002256249  85 QRARESFLKEFDAQKMRLPDSSNVDSLREFIKAVYVERRYAGGRFSERPPRDKQNQKNNEQEHRRASSYHSFSQSPPYDY 164
Cdd:PLN03119   82 QRAREIYLKNWDHQRQRLPENSNAERVREFIKNVYVQKKYAGANDADKPSKDSQDHVSSEDMTRRANSYHSYSQSPPYDY 161

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002256249 165 QYEERRNGKQSVMLTRKPGSDRGHDGKMSGFAYSPQSLHERMSEDRFANENSGPRISDCSGSSISNTFRTTPHSPNFLDK 244
Cdd:PLN03119  162 QYEERRYGKIPLGFTGKSASVKGLHAKASSFVYSPGRFSDHMFEDQFSNEDSAPRASDYSVSSAGDPFRSDIQSPNFQQE 241

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002256249 245 G-CSSPSMQqnQSNIQASSGI---TQSERTISTGNIDSSSTKS------SKSSLADMFFESDIAHRTQQTKDCITPSFTA 314
Cdd:PLN03119  242 AeFRSPQFQ--HSNAPPSENLfpgRQHQRTTSSGSVRSVDSNFmsiksyTSGGLGEAVSESRQNTGSQQGKTSNHVPLVA 319

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002256249 315 FSDVANIAQKDLLNEPVAQ-------------------QQPVTGLDQPVDFFASMPPATPSTDRMLTAAPSmdNAGWATF 375
Cdd:PLN03119  320 ESTKAPIDLFQLPGAPVAQsvdtfqpsiaprsppvnlqQAPQTYSFTPANSFAGNLGQQPTSRPSELSAPK--NEGWASF 397

                         410       420       430       440       450       460       470       480
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002256249 376 DTP-PEEKQPGVIGLSGIsvmdkhalsgdlFSFEPNNDQPTWLQSSKTSKNNASVTDQSDV----PCKYTSSD-----AS 445
Cdd:PLN03119  398 DNPmPAAKSTNVITSPGD------------FQLELKIEEILQPSTSMQLPPYPSTVDQHALsipsPWQEDLSNvlkdvVD 465

                         490       500       510       520       530       540       550       560
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002256249 446 NSQAWSAFeaksvstqqasPDlslmsSIEPKePIDENKLQlwHSFDDASETMTLNLSNAQLQTNEHKNESR-GNDSQEIF 524
Cdd:PLN03119  466 NPQPWNAF-----------PD-----SIEAN-PLDSSRNI--HQQVDGASTSSYNTDHQHLESQVLEELSNdGTQTTRIP 526

                         570       580       590       600       610       620       630       640
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002256249 525 MGGLAPSEPFAPFPEPSLfaTTSVGEASVQQMPLNPFDLPFDADSDSPDMFMDVTALQAVLPNADLSTSFVDGLPETWFS 604
Cdd:PLN03119  527 AGSSAFGFPGNIGMAPSY--SEEAWQHVNEQKSANPFDLPYDSEFDSNDMFLDMSSLQGALPDIQTPQAFLNGVSQPWLA 604

                         650       660       670       680
                  ....*....|....*....|....*....|....*....|....*.
gi 1002256249 605 -NNASAYVPPG--SHGGPPCLVEQIP-NSALRNITlsAVSTGNPFA 646
Cdd:PLN03119  605 aDSVPSYLPAPavAQGGLAYMAGQAStNSAAQGPV--AFTGGNPFA 648

Putative GTPase activating protein for 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 1002256249  14 ERVVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF---THRVKSVSMSTFTTQEVEALQNGGNQRARES 90
Cdd:pfam01412   1 KRVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLgvhISKVRSLTLDTWTDEQLELMKAGGNDRANEF 80

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1002256249  91 FLKEFDAQKMRLPDSSNVDsLREFIKAVYVERRYA 125
Cdd:pfam01412  81 WEANLPPSYKPPPSSDREK-RESFIRAKYVEKKFA 114

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 1002256249  15 RVVRGLLKLPP-NRRCINCNGLGPQYVCTSFWTFVCISCSGIHREFT--HRVKSVSMSTFTTQEVEALQNGGNQRARESF 91
Cdd:cd17903     2 RRVRELGGCSAaNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNppHRVKSISMTTFTEPEVLFLQARGNEVCRKIW 81

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1002256249  92 LKEFDAQKMRLPDSSNVDSLREFIKAVYVERRY 124
Cdd:cd17903    82 LGLFDARTSLIPDSRDPQKVKEFLQEKYEKKRW 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 1002256249  20 LLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF-TH--RVKSVSMSTFTTQEVEALQNGGNQRARESFLKEFD 96
Cdd:cd08204     4 LLKLPGNKVCADCGAPDPRWASINLGVFICIRCSGIHRSLgVHisKVRSLTLDSWTPEQVELMKAIGNARANAYYEANLP 83

                          90       100
                  ....*....|....*....|...
gi 1002256249  97 AQKMRLPDSSNVDSLREFIKAVY 119
Cdd:cd08204    84 PGFKKPTPDSSDEEREQFIRAKY 106

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 1002256249  15 RVVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF-THR--VKSVSMSTFTTQEVEALQNGGNQRAREsF 91
Cdd:cd08830     3 AVLRELQKLPGNNRCFDCGAPNPQWASVSYGIFICLECSGVHRGLgVHIsfVRSITMDSWSEKQLKKMELGGNAKLRE-F 81

                  ...
gi 1002256249  92 LKE 94
Cdd:cd08830    82 FES 84

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 1002256249  15 RVVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHR------EFthrVKSVSMSTFTTQEVEALQNGGNQRAR 88
Cdd:cd08959     3 AVFKKLRSKPENKVCFDCGAKNPQWASVTYGIFICLDCSGVHRglgvhiSF---VRSTTMDKWTEEQLRKMKVGGNANAR 79

                  ....*.
gi 1002256249  89 EsFLKE 94
Cdd:cd08959    80 E-FFKQ 84

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 1002256249  16 VVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF-TH--RVKSVSMSTFTTQEVEALQNGGNQRARESFl 92
Cdd:cd08834     5 IIAEVKRLPGNDVCCDCGSPDPTWLSTNLGILTCIECSGVHRELgVHvsRIQSLTLDNLGTSELLLARNLGNEGFNEIM- 83

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1002256249  93 kEFDAQKMRLPD-SSNVDSLREFIKAVYVERRYA 125
Cdd:cd08834    84 -EANLPPGYKPTpNSDMEERKDFIRAKYVEKKFV 116

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 1002256249  13 NERVVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREFT---HRVKSVSMSTFTTQEVEALQNGGNQRARE 89
Cdd:cd17900     2 TKLLIAEVKSRPGNSQCCDCGAPDPTWLSTNLGILTCIECSGIHRELGvrySRIQSLTLDLLSTSELLLAVSMGNTRFNE 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1002256249  90 SFLKEFDAQKMRLPD-SSNVDSLREFIKAVYVERRYAggRFSERP 133
Cdd:cd17900    82 VMEATLPAHGGPKPSaESDMGTRKDYIMAKYVEHRFV--RKRCTP 124

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 1002256249  10 EERNERVVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHRE-FTH--RVKSVSMSTFTTQEVEALQNGGNQR 86
Cdd:COG5347     4 KSEDRKLLKLLKSDSSNKKCADCGAPNPTWASVNLGVFLCIDCAGVHRSlGVHisKVKSLTLDNWTEEELRRMEVGGNSN 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002256249  87 ARESFLKE---FDAQKMRLPDSSNVdsLREFIKAVYVERRYAGGRFSERPPRDKQNQKNNE-------QEHRRASSYHSF 156
Cdd:COG5347    84 ANRFYEKNlldQLLLPIKAKYDSSV--AKKYIRKKYELKKFIDDSSSPSDFSSFSASSTRTvdsvddrLDSESQSRSSSA 161

                         170       180
                  ....*....|....*....|..
gi 1002256249 157 SQSPPYDYQYEERRNGKQSVML 178
Cdd:COG5347   162 SLGNSNRPDDELNVESFQSTGS 183

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 1002256249  22 KLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF-TH--RVKSVSMSTFTTQEVEALQNGGNQRARESFLKEFDAQ 98
Cdd:cd08849    11 RMTGNDVCCDCGAPDPTWLSTNLGILTCIECSGIHRELgVHysRMQSLTLDVLGTSELLLAKNIGNAGFNEIMEACLPAE 90

                          90       100
                  ....*....|....*....|....*...
gi 1002256249  99 KMRLPD-SSNVDSLREFIKAVYVERRYA 125
Cdd:cd08849    91 DVVKPNpGSDMNARKDYITAKYIERRYA 118

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 1002256249  14 ERVVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF---THRVKSVSMSTFTTQEVEALQNGGNQRAR-- 88
Cdd:cd08835     1 GSALEQVLSVPGNAQCCDCGSPDPRWASINLGVTLCIECSGIHRSLgvhVSKVRSLTLDSWEPELLKVMLELGNDVVNri 80

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1002256249  89 -ESFLKEFDAQKMrLPDSSNvdSLRE-FIKAVYVERRYA 125
Cdd:cd08835    81 yEANVPDDGSVKP-TPDSSR--QEREaWIRAKYVEKKFV 116

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 1002256249  14 ERVVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF-TH--RVKSVSMSTFTTQEVEALQNGGNQRARES 90
Cdd:cd08850     1 ESILQRVQSIAGNDQCCDCGQPDPRWASINLGILLCIECSGIHRSLgVHcsKVRSLTLDSWEPELLKLMCELGNSTVNQI 80

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1002256249  91 FLKEFDAQKMRLPDSSNVDSLRE-FIKAVYVERRY 124
Cdd:cd08850    81 YEAQCEELGLKKPTASSSRQDKEaWIKAKYVEKKF 115

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 1002256249  23 LPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF-TH--RVKSVSMSTFTTQEVEALQNGGN---QRARESFLKEFD 96
Cdd:cd08851    10 IPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLgVHfsKVRSLTLDTWEPELLKLMCELGNdviNRIYEARVEKMG 89

                          90       100
                  ....*....|....*....|....*...
gi 1002256249  97 AQKMRLPDSSNvdSLREFIKAVYVERRY 124
Cdd:cd08851    90 AKKPQPGGQRQ--EKEAYIRAKYVERKF 115

Arf1 GTPase-activating protein 2; 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 1002256249  16 VVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF-THR--VKSVSM-STFTTQEVEALQNGGNQRARESF 91
Cdd:cd09029     9 LFKRLRAIPTNKACFDCGAKNPSWASITYGVFLCIDCSGVHRSLgVHLsfIRSTELdSNWNWFQLRCMQVGGNANATAFF 88

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 1002256249  16 VVRGLLKLPPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF-THR--VKSVSM-STFTTQEVEALQNGGNQRARESF 91
Cdd:cd09028     9 IFKRLRSVPTNKVCFDCGAKNPSWASITYGVFLCIDCSGIHRSLgVHLsfIRSTELdSNWSWFQLRCMQVGGNANASAFF 88

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 1002256249  26 NRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF-TH--RVKSVSMSTFTTQEVEALQNGGNQRARESFlkEFDAQKMRL 102
Cdd:cd08854    13 NSLCVDCGAPNPTWASLNLGALICIECSGIHRNLgTHlsRVRSLDLDDWPRELTLVLTAIGNHMANSIW--ESCTQGRTK 90

                          90
                  ....*....|....*...
gi 1002256249 103 PDSSNVDSLRE-FIKAVY 119
Cdd:cd08854    91 PAPDSSREEREsWIRAKY 108

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002256249  24 PPNRRCINCNGLGPQYVCTSFWTFVCISCSGIHREF---THRVKSVSMS--TFTTQEVEALQNGGNQRARESFLKEFDAQ 98
Cdd:cd17901    11 ESNRFCADCGSPKPDWASVNLCVVICKRCAGEHRGLgpsVSKVRSLKMDrkVWTEELIELFLLLGNGKANQFWAANVPPS 90

                          90       100
                  ....*....|....*....|....*.
gi 1002256249  99 KMRLPdSSNVDSLREFIKAVYVERRY 124
Cdd:cd17901    91 EALCP-SSSSEERRHFITAKYKEGKY 115