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 147902573  13 HLKMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPPHRVKSISMTTFTQQEIEFLQKHGNDVCKQI 92
Cdd:cd08857    1 HLKMLREMTSLPHNRKCFDCDQRGPTYANMTVGSFVCTSCSGILRGLNPPHRVKSISMTTFTQQEIEFLQKHGNEVCKQI 80

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 147902573  93 WLGLFDDRSSAIPDFRDPQKVKEFLQEKYEKKRWYV 128
Cdd:cd08857   81 WLGLFDDRSSAIPDFRDPQKVKEFLQEKYEKKRWYV 116

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 147902573  13 HLKMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPPHRVKSISMTTFTQQEIEFLQKHGNDVCKQI 92
Cdd:cd08857    1 HLKMLREMTSLPHNRKCFDCDQRGPTYANMTVGSFVCTSCSGILRGLNPPHRVKSISMTTFTQQEIEFLQKHGNEVCKQI 80

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 147902573  93 WLGLFDDRSSAIPDFRDPQKVKEFLQEKYEKKRWYV 128
Cdd:cd08857   81 WLGLFDDRSSAIPDFRDPQKVKEFLQEKYEKKRWYV 116

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 147902573   15 KMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGL-NPPHRVKSISMTTFTQQEIEFLQKHGNDVCKQIW 93
Cdd:pfam01412   2 RVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLgVHISKVRSLTLDTWTDEQLELMKAGGNDRANEFW 81

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 147902573   94 LGLFDDrSSAIPDFRDPQKVKEFLQEKYEKKRWYVPP 130
Cdd:pfam01412  82 EANLPP-SYKPPPSSDREKRESFIRAKYVEKKFAKPG 117

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 147902573   8 KQEEKHLKMLREMtsLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNpPH--RVKSISMTTFTQQEIEFLQKHG 85
Cdd:COG5347    4 KSEDRKLLKLLKS--DSSNKKCADCGAPNPTWASVNLGVFLCIDCAGVHRSLG-VHisKVKSLTLDNWTEEELRRMEVGG 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 147902573  86 NDVCKQIWLGlfDDRSSAIPDFR---DPQKVKEFLQEKYEKKRW 126
Cdd:COG5347   81 NSNANRFYEK--NLLDQLLLPIKakyDSSVAKKYIRKKYELKKF 122

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 147902573  13 HLKMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPPHRVKSISMTTFTQQEIEFLQKHGNDVCKQI 92
Cdd:cd08857    1 HLKMLREMTSLPHNRKCFDCDQRGPTYANMTVGSFVCTSCSGILRGLNPPHRVKSISMTTFTQQEIEFLQKHGNEVCKQI 80

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 147902573  93 WLGLFDDRSSAIPDFRDPQKVKEFLQEKYEKKRWYV 128
Cdd:cd08857   81 WLGLFDDRSSAIPDFRDPQKVKEFLQEKYEKKRWYV 116

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 147902573  15 KMLREMT-SLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPPHRVKSISMTTFTQQEIEFLQKHGNDVCKQIW 93
Cdd:cd17903    2 RRVRELGgCSAANRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPPHRVKSISMTTFTEPEVLFLQARGNEVCRKIW 81

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 147902573  94 LGLFDDRSSAIPDFRDPQKVKEFLQEKYEKKRWYV 128
Cdd:cd17903   82 LGLFDARTSLIPDSRDPQKVKEFLQEKYEKKRWYV 116

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 147902573   15 KMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGL-NPPHRVKSISMTTFTQQEIEFLQKHGNDVCKQIW 93
Cdd:pfam01412   2 RVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLgVHISKVRSLTLDTWTDEQLELMKAGGNDRANEFW 81

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 147902573   94 LGLFDDrSSAIPDFRDPQKVKEFLQEKYEKKRWYVPP 130
Cdd:pfam01412  82 EANLPP-SYKPPPSSDREKRESFIRAKYVEKKFAKPG 117

hypothetical protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 147902573   7 RKQEEKHLKMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNppHRVKSISMTTFTQQEIEFLQKHGN 86
Cdd:PLN03131   4 RKEEERNEKIIRGLMKLPPNRRCINCNSLGPQFVCTNFWTFICMTCSGIHREFT--HRVKSVSMSKFTSQDVEALQNGGN 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 147902573  87 DVCKQIWLGLFDDRSSAIPDFRDPQKVKEFLQEKYEKKRW 126
Cdd:PLN03131  82 QRAREIYLKDWDQQRQRLPDNSKVDKIREFIKDIYVDKKY 121

ArfGap with dual PH domains; The ADAP subfamily, ArfGAPs with dual pleckstrin homology (PH) domains, includes two members: ADAP1 and ADAP2. Both ADAP1 (also known as centaurin-alpha1, p42(IP4), or PIP3BP) and ADAP2 (centaurin-alpha2) display a GTPase-activating protein (GAP) activity toward Arf6 (ADP-ribosylation factor 6), which is involved in protein trafficking that regulates endocytic recycling, cytoskeleton remodeling, and neuronal differentiation. ADAP2 has high sequence similarity to the ADAP1 and they both contain a ArfGAP domain at the N-terminus, followed by two PH domains. However, ADAP1, unlike ADAP2, contains a putative N-terminal nuclear localization signal. The PH domains of ADAP1bind to the two second messenger molecules phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with identical high affinity, whereas those of ADAP2 specifically binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and PI(3,4,5)P3, which are produced by activated phosphatidylinositol 3-kinase. ADAP1 is predominantly expressed in the brain neurons, while ADAP2 is broadly expressed, including the adipocytes, heart, and skeletal muscle but not in the brain. The limited distribution and high expression of ADAP1 in the brain indicates that ADAP1 is important for neuronal functions. ADAP1 has been shown to highly expressed in the neurons and plagues of Alzheimer's disease patients. In other hand, ADAP2 gene deletion has been shown to cause circulatory deficiencies and heart shape defects in zebrafish, indicating that ADAP2 has a vital role in heart development. Taken together, the hemizygous deletion of ADAP2 gene may be contributing to the cardiovascular malformation in patients with neurofibromatosis type 1 (NF1) microdeletions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 147902573  11 EKHLKMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLnPPH--RVKSISMTTFTQQEIEFLQKHGNDV 88
Cdd:cd08832    2 ERNKKRLLELLKLPGNNTCADCGAPDPEWASYNLGVFICLDCSGIHRSL-GTHisKVKSLRLDNWDDSQVEFMEENGNEK 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 147902573  89 CKQIWlglfddrSSAIPDF------RDPQKVKE-FLQEKY 121
Cdd:cd08832   81 AKAKY-------EAHVPAFyrrptpTDPQVLREqWIRAKY 113

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 147902573   8 KQEEKHLKMLREMtsLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNpPH--RVKSISMTTFTQQEIEFLQKHG 85
Cdd:COG5347    4 KSEDRKLLKLLKS--DSSNKKCADCGAPNPTWASVNLGVFLCIDCAGVHRSLG-VHisKVKSLTLDNWTEEELRRMEVGG 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 147902573  86 NDVCKQIWLGlfDDRSSAIPDFR---DPQKVKEFLQEKYEKKRW 126
Cdd:COG5347   81 NSNANRFYEK--NLLDQLLLPIKakyDSSVAKKYIRKKYELKKF 122

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 147902573  15 KMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNpPHR--VKSISMTTFTQQEIEFLQKHGNDVCKQ 91
Cdd:cd08830    3 AVLRELQKLPGNNRCFDCGAPNPQWASVSYGIFICLECSGVHRGLG-VHIsfVRSITMDSWSEKQLKKMELGGNAKLRE 80

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 147902573  15 KMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNpPHR--VKSISMTTFTQQEIEFLQKHGNDVCKQ 91
Cdd:cd08959    3 AVFKKLRSKPENKVCFDCGAKNPQWASVTYGIFICLDCSGVHRGLG-VHIsfVRSTTMDKWTEEQLRKMKVGGNANARE 80

ADAP2 GTPase activating protein for Arf, with dual PH domains; The ADAP subfamily, ArfGAPs with dual pleckstrin homology (PH) domains, includes two members: ADAP1 and ADAP2. Both ADAP1 (also known as centaurin-alpha1, p42(IP4), or PIP3BP) and ADAP2 (centaurin-alpha2) display a GTPase-activating protein (GAP) activity toward Arf6 (ADP-ribosylation factor 6), which is involved in protein trafficking that regulates endocytic recycling, cytoskeleton remodeling, and neuronal differentiation. ADAP2 has high sequence similarity to the ADAP1 and they both contain a ArfGAP domain at the N-terminus, followed by two PH domains. However, ADAP1, unlike ADAP2, contains a putative N-terminal nuclear localization signal. The PH domains of ADAP1bind to the two second messenger molecules phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with identical high affinity, whereas those of ADAP2 specifically binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and PI(3,4,5)P3, which are produced by activated phosphatidylinositol 3-kinase. ADAP1 is predominantly expressed in the brain neurons, while ADAP2 is broadly expressed, including the adipocytes, heart, and skeletal muscle but not in the brain. The limited distribution and high expression of ADAP1 in the brain indicates that ADAP1 is important for neuronal functions. ADAP1 has been shown to highly expressed in the neurons and plagues of Alzheimer's disease patients. In other hand, ADAP2 gene deletion has been shown to cause circulatory deficiencies and heart shape defects in zebrafish, indicating that ADAP2 has a vital role in heart development. Taken together, the hemizygous deletion of ADAP2 gene may be contributing to the cardiovascular malformation in patients with neurofibromatosis type 1 (NF1) microdeletions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 147902573  11 EKHLKMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPPHRVKSISMTTFTQQEIEFLQKHGNDVCK 90
Cdd:cd08844    2 DRNKKRLLELLKLPGNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLPDISRVKSIRLDFWEDELVEFMKENGNLKAK 81

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 147902573  16 MLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNpPH--RVKSISMTTFTQQEIEFLQKHGNDVCKQIW 93
Cdd:cd08850    3 ILQRVQSIAGNDQCCDCGQPDPRWASINLGILLCIECSGIHRSLG-VHcsKVRSLTLDSWEPELLKLMCELGNSTVNQIY 81

                         90       100       110
                 ....*....|....*....|....*....|....
gi 147902573  94 LGLFDDRSSAIPDFRDPQKVKE-FLQEKYEKKRW 126
Cdd:cd08850   82 EAQCEELGLKKPTASSSRQDKEaWIKAKYVEKKF 115

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 147902573  17 LREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNpPH--RVKSISMTTFTQQEIEFLQKHGNDVCKQIWL 94
Cdd:cd08836    3 LQAIRNVRGNDHCVDCGAPNPDWASLNLGALMCIECSGIHRNLG-THisRVRSLDLDDWPVELLKVMSAIGNDLANSVWE 81

                         90       100
                 ....*....|....*....|....*....
gi 147902573  95 GLFDDRSSaiPDFRDPQKVKE-FLQEKYE 122
Cdd:cd08836   82 GNTQGRTK--PTPDSSREEKErWIRAKYE 108

ArfGAP domain of ACAP1 (ArfGAP with Coiled-coil, ANK repeat and PH domains 1); ACAP1 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 147902573  17 LREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNpPH--RVKSISMTTFTQQEIEFLQKHGNDVCKQIWL 94
Cdd:cd08852    4 VAQVQSVDGNAQCCDCREPAPEWASINLGVTLCIQCSGIHRSLG-VHfsKVRSLTLDSWEPELVKLMCELGNVIINQIYE 82

                         90       100       110
                 ....*....|....*....|....*....|...
gi 147902573  95 GLFDDRSSAIPDFRDPQKVKE-FLQEKYEKKRW 126
Cdd:cd08852   83 ARIEAMAIKKPGPSSSRQEKEaWIRAKYVEKKF 115

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 147902573  26 NRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPP-HRVKSISMTTFTQQEIEFLQKHGNDVCKQIWLGLFDDRSSAI 104
Cdd:cd08855   14 NSFCIDCDAPNPDWASLNLGALMCIECSGIHRNLGTHlSRVRSLDLDDWPVELSMVMTAIGNAMANSVWEGALDGYSKPG 93

                         90
                 ....*....|....*...
gi 147902573 105 PDFRDPQKvKEFLQEKYE 122
Cdd:cd08855   94 PDSTREEK-ERWIRAKYE 110

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 147902573  22 SLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPP-HRVKSISM--TTFTQQEIEFLQKHGNDVCKQIWlGLFD 98
Cdd:cd17901    9 SVESNRFCADCGSPKPDWASVNLCVVICKRCAGEHRGLGPSvSKVRSLKMdrKVWTEELIELFLLLGNGKANQFW-AANV 87

                         90       100
                 ....*....|....*....|....*...
gi 147902573  99 DRSSAIPDFRDPQKVKEFLQEKYEKKRW 126
Cdd:cd17901   88 PPSEALCPSSSSEERRHFITAKYKEGKY 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
                 ....*....|....*....|....*....|....*....|....
gi 147902573  16 MLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGL 59
Cdd:cd09029    9 LFKRLRAIPTNKACFDCGAKNPSWASITYGVFLCIDCSGVHRSL 52

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 147902573  20 MTSLPHNRK-CFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPP-HRVKSISMTTFTQQEIEFLQKHGNDVCKQIW-LGL 96
Cdd:cd08833    1 IRGKSSNARvCADCSAPDPEWASINRGVLICDECCSIHRSLGRHiSQVKSLRKDQWPPSLLEMVQTLGNNGANSIWeHSL 80

                         90       100       110
                 ....*....|....*....|....*....|
gi 147902573  97 FDDRSSAI-----PDFRDPQKvKEFLQEKY 121
Cdd:cd08833   81 LDPSQSGKrkpipPDPVHPTK-EEFIKAKY 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 147902573  15 KMLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPPH-RVKSISMTTFTQQEIEFLQKHGNDVCKQIW 93
Cdd:cd08849    4 EIISEVQRMTGNDVCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVHYsRMQSLTLDVLGTSELLLAKNIGNAGFNEIM 83

                         90       100       110
                 ....*....|....*....|....*....|....
gi 147902573  94 LGLFDDRSSAIPD-FRDPQKVKEFLQEKYEKKRW 126
Cdd:cd08849   84 EACLPAEDVVKPNpGSDMNARKDYITAKYIERRY 117

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 147902573  16 MLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPP-HRVKSISMTTFTQQEIEFLQKHGNDVCKQIWL 94
Cdd:cd08848    5 IIDDVQRLPGNEVCCDCGSPDPTWLSTNLGILTCIECSGIHREMGVHiSRIQSLELDKLGTSELLLAKNVGNNSFNDIME 84

                         90       100       110
                 ....*....|....*....|....*....|..
gi 147902573  95 GLFDDRSSAIPDFRDPQKVKEFLQEKYEKKRW 126
Cdd:cd08848   85 GNLPSPSPKPSPSSDMTARKEYITAKYVEHRF 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 147902573  16 MLREMTSLPHNRKCFDCDQRGPTYANMTTGAFVCTSCSGILRGLNPPH-RVKSISMTTFTQQEIEFLQKHGNDVCKQIWL 94
Cdd:cd17900    5 LIAEVKSRPGNSQCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVRYsRIQSLTLDLLSTSELLLAVSMGNTRFNEVME 84

                         90       100       110
                 ....*....|....*....|....*....|...
gi 147902573  95 GLFDDRSSAIPDFR-DPQKVKEFLQEKYEKKRW 126
Cdd:cd17900   85 ATLPAHGGPKPSAEsDMGTRKDYIMAKYVEHRF 117

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 147902573  349 STSVPASSGPAVPAPADNHVFGLGSAAHTHTVASAAGPFAAPASTNPFVSASVAPAVNPFQTNG----------RAPPGL 418
Cdd:PHA03247 2790 SLSESRESLPSPWDPADPPAAVLAPAAALPPAASPAGPLPPPTSAQPTAPPPPPGPPPPSLPLGgsvapggdvrRRPPSR 2869

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 147902573  419 QDGHRAEAPFHAfHQTRLATAAGALDASSFGTASHS---MPAGFGTQTPYSLPTSFSGSFHQPAFPPQTAFPQQTAFSQQ 495
Cdd:PHA03247 2870 SPAAKPAAPARP-PVRRLARPAVSRSTESFALPPDQperPPQPQAPPPPQPQPQPPPPPQPQPPPPPPPRPQPPLAPTTD 2948

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....
gi 147902573  496 PNGNIQGAGFAVFGQIKPVVTpfGQVSAPgvssnPFMAGAPSGQFPTGSSSTNP 549
Cdd:PHA03247 2949 PAGAGEPSGAVPQPWLGALVP--GRVAVP-----RFRVPQPAPSREAPASSTPP 2995