large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  146 VPPEQVKG--PSYSKGSVSATPVQGSVPegkPIRTLLGDPVPSLSDPASTSSQPGSQSQARSSSQARSSQPPSHSSTKKA 223
Cdd:PHA03247 2591 APPQSARPraPVDDRGDPRGPAPPSPLP---PDTHAPDPPPPSPSPAANEPDPHPPPTVPPPERPRDDPAPGRVSRPRRA 2667

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  224 STDLLADIGGDPFAAPQ---VVPAFASFPGFG----VGQTPAHGGFANFDAFSSSPSSSTFGSLPPSVQAPFQAQPTPAA 296
Cdd:PHA03247 2668 RRLGRAAQASSPPQRPRrraARPTVGSLTSLAdpppPPPTPEPAPHALVSATPLPPGPAAARQASPALPAAPAPPAVPAG 2747

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  297 NRMLTGSYSFGSGQMSAFGVAPL-----AAASQPNNLADVGGLLGPRMAAGGLPGSVFGMPSQVPALQSAVPGVSG-SGG 370
Cdd:PHA03247 2748 PATPGGPARPARPPTTAGPPAPAppaapAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASpAGP 2827

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  371 LPfgaytnPFATPAQAQLPSTNPFQPNGLASGpgfgmSSVRPG-LLQPVPPSGAFASPFSAPVFPTQAGLADQQNGSSFG 449
Cdd:PHA03247 2828 LP------PPTSAQPTAPPPPPGPPPPSLPLG-----GSVAPGgDVRRRPPSRSPAAKPAAPARPPVRRLARPAVSRSTE 2896

                         330
                  ....*....|....*.
gi 740087244  450 DLGTSKLGQRPLSQPA 465
Cdd:PHA03247 2897 SFALPPDQPERPPQPQ 2912

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 740087244    40 SQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPpHR--VKSISMTTFTEPEVLFLQSRGNEVCRKIWLGLFDA 117
Cdd:smart00105   6 SIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSLGV-HIskVRSLTLDTWTEEELRLLQKGGNENANSIWESNLDD 84

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 740087244   118 RTSLIPDSRDPQKVKEFLQEKYEKKRWyVPPEQVK 152
Cdd:smart00105  85 FSLKPPDDDDQQKYESFIAAKYEEKLF-VPPESAE 118

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 740087244  40 SQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNpPH--RVKSISMTTFTEPEVLFLQSRGNEVCRKIWLG---- 113
Cdd:COG5347   16 SDSSNKKCADCGAPNPTWASVNLGVFLCIDCAGVHRSLG-VHisKVKSLTLDNWTEEELRRMEVGGNSNANRFYEKnlld 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244 114 --LFDARTslIPDSrdpQKVKEFLQEKYEKKRWYVPPeqvkgpsySKGSVSATPVQGSVPEGKPIRTLLgdpvPSLSDPA 191
Cdd:COG5347   95 qlLLPIKA--KYDS---SVAKKYIRKKYELKKFIDDS--------SSPSDFSSFSASSTRTVDSVDDRL----DSESQSR 157

                 ....
gi 740087244 192 STSS 195
Cdd:COG5347  158 SSSA 161

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  146 VPPEQVKG--PSYSKGSVSATPVQGSVPegkPIRTLLGDPVPSLSDPASTSSQPGSQSQARSSSQARSSQPPSHSSTKKA 223
Cdd:PHA03247 2591 APPQSARPraPVDDRGDPRGPAPPSPLP---PDTHAPDPPPPSPSPAANEPDPHPPPTVPPPERPRDDPAPGRVSRPRRA 2667

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  224 STDLLADIGGDPFAAPQ---VVPAFASFPGFG----VGQTPAHGGFANFDAFSSSPSSSTFGSLPPSVQAPFQAQPTPAA 296
Cdd:PHA03247 2668 RRLGRAAQASSPPQRPRrraARPTVGSLTSLAdpppPPPTPEPAPHALVSATPLPPGPAAARQASPALPAAPAPPAVPAG 2747

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  297 NRMLTGSYSFGSGQMSAFGVAPL-----AAASQPNNLADVGGLLGPRMAAGGLPGSVFGMPSQVPALQSAVPGVSG-SGG 370
Cdd:PHA03247 2748 PATPGGPARPARPPTTAGPPAPAppaapAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASpAGP 2827

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  371 LPfgaytnPFATPAQAQLPSTNPFQPNGLASGpgfgmSSVRPG-LLQPVPPSGAFASPFSAPVFPTQAGLADQQNGSSFG 449
Cdd:PHA03247 2828 LP------PPTSAQPTAPPPPPGPPPPSLPLG-----GSVAPGgDVRRRPPSRSPAAKPAAPARPPVRRLARPAVSRSTE 2896

                         330
                  ....*....|....*.
gi 740087244  450 DLGTSKLGQRPLSQPA 465
Cdd:PHA03247 2897 SFALPPDQPERPPQPQ 2912

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 740087244  31 RRVRELGgcSQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNppHRVKSISMTTFTEPEVLFLQSRGNEVCRKI 110
Cdd:cd08838    2 KILRELL--KLPENKRCFDCGQRGPTYVNLTFGTFVCTTCSGIHREFN--HRVKSISMSTFTPEEVEFLQAGGNEVARKI 77

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 740087244 111 WLGLFDARTSLIPDSRDPQKVKEFLQEKYEKKRWYV 146
Cdd:cd08838   78 WLAKWDPRTDPEPDSGDDQKIREFIRLKYVDKRWYD 113

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 740087244    40 SQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPpHR--VKSISMTTFTEPEVLFLQSRGNEVCRKIWLGLFDA 117
Cdd:smart00105   6 SIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSLGV-HIskVRSLTLDTWTEEELRLLQKGGNENANSIWESNLDD 84

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 740087244   118 RTSLIPDSRDPQKVKEFLQEKYEKKRWyVPPEQVK 152
Cdd:smart00105  85 FSLKPPDDDDQQKYESFIAAKYEEKLF-VPPESAE 118

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 740087244  40 SQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLnPPH--RVKSISMTTFTEPEVLFLQSRGNEVCRKIWLGLFDA 117
Cdd:cd08204    6 KLPGNKVCADCGAPDPRWASINLGVFICIRCSGIHRSL-GVHisKVRSLTLDSWTPEQVELMKAIGNARANAYYEANLPP 84

                         90       100
                 ....*....|....*....|..
gi 740087244 118 RTSLIPDSRDPQKVKEFLQEKY 139
Cdd:cd08204   85 GFKKPTPDSSDEEREQFIRAKY 106

hypothetical protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  44 NRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNppHRVKSISMTTFTEPEVLFLQSRGNEVCRKIWLGLFDARTSLIP 123
Cdd:PLN03131  23 NRRCINCNSLGPQFVCTNFWTFICMTCSGIHREFT--HRVKSVSMSKFTSQDVEALQNGGNQRAREIYLKDWDQQRQRLP 100

                         90       100
                 ....*....|....*....|.
gi 740087244 124 DSRDPQKVKEFLQEKYEKKRW 144
Cdd:PLN03131 101 DNSKVDKIREFIKDIYVDKKY 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 740087244  31 RRVRELggCSQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLnPPH--RVKSISMTTFTEPEVLFLQSRGNEVCR 108
Cdd:cd08832    6 KRLLEL--LKLPGNNTCADCGAPDPEWASYNLGVFICLDCSGIHRSL-GTHisKVKSLRLDNWDDSQVEFMEENGNEKAK 82

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 740087244 109 KIWlglfDARTSL---IPDSRDPQKVKE-FLQEKY 139
Cdd:cd08832   83 AKY----EAHVPAfyrRPTPTDPQVLREqWIRAKY 113

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  43 GNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNpPH--RVKSISMTTFTEPEVLFLQSRGNEVCRKIWlglfDArtS 120
Cdd:cd08839    9 DNKYCADCGAKGPRWASWNLGVFICIRCAGIHRNLG-VHisKVKSVNLDSWTPEQVQSMQEMGNARANAYY----EA--N 81

                         90       100
                 ....*....|....*....|..
gi 740087244 121 LIPDSRDPQ---KVKEFLQEKY 139
Cdd:cd08839   82 LPDGFRRPQtdsALENFIRDKY 103

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 740087244  40 SQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNpPHR--VKSISMTTFTEPEVLFLQSRGNEVCR 108
Cdd:cd08830   10 KLPGNNRCFDCGAPNPQWASVSYGIFICLECSGVHRGLG-VHIsfVRSITMDSWSEKQLKKMELGGNAKLR 79

ADAP1 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 740087244  31 RRVRELggCSQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPPHRVKSISMTTFTEPEVLFLQSRGNEVCRki 110
Cdd:cd08843    6 RAVLEL--LQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQVSKVKSVRLDAWEEAQVEFMASHGNDAAR-- 81

                         90       100       110
                 ....*....|....*....|....*....|...
gi 740087244 111 wlGLFDARTSLI---PDSRDPQKVKE-FLQEKY 139
Cdd:cd08843   82 --ARFESKVPSFyyrPTPSDCQLLREqWIRAKY 112

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 740087244  40 SQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNpPH--RVKSISMTTFTEPEVLFLQSRGNEVCRKIW---LGL 114
Cdd:cd08831   11 SKPENKVCFDCGAKNPTWASVTFGVFLCLDCSGVHRSLG-VHisFVRSTNLDSWTPEQLRRMKVGGNAKAREFFkqhGGL 89

                         90       100
                 ....*....|....*....|....*..
gi 740087244 115 FDARTSLIPDSRDPQKVKEFLQEKYEK 141
Cdd:cd08831   90 LSGDIKQKYTSRAAQKYKEKLDKLVAK 116

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 740087244  40 SQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNpPHR--VKSISMTTFTEPEVLFLQSRGNEVCRK 109
Cdd:cd08959   10 SKPENKVCFDCGAKNPQWASVTYGIFICLDCSGVHRGLG-VHIsfVRSTTMDKWTEEQLRKMKVGGNANARE 80

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing proteins; 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244  23 EAASEVWcrrvrelggcSQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPP-HRVKSISMTT--FTEPEVLFL 99
Cdd:cd08837    2 EVAEKIW----------SNPANRFCADCGAPDPDWASINLCVVICKQCAGEHRSLGSNiSKVRSLKMDTkvWTEELVELF 71

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 740087244 100 QSRGNEVCRKIWLGLFDARTSLIPDSrDPQKVKEFLQEKYEKKRW 144
Cdd:cd08837   72 LKLGNDRANRFWAANLPPSEALHPDA-DSEQRREFITAKYREGKY 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 740087244  42 AGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPpH--RVKSISMTTFTEPEVLFLQSRGNEVCRKIWLGLFDART 119
Cdd:cd08836   10 RGNDHCVDCGAPNPDWASLNLGALMCIECSGIHRNLGT-HisRVRSLDLDDWPVELLKVMSAIGNDLANSVWEGNTQGRT 88

                         90       100
                 ....*....|....*....|..
gi 740087244 120 SLIPDSrdPQKVKE-FLQEKYE 140
Cdd:cd08836   89 KPTPDS--SREEKErWIRAKYE 108

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 740087244  42 AGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNpPH--RVKSISMTTFtEPEVLFLQSR-GNEVCRKIWLGLFDAR 118
Cdd:cd08835   11 PGNAQCCDCGSPDPRWASINLGVTLCIECSGIHRSLG-VHvsKVRSLTLDSW-EPELLKVMLElGNDVVNRIYEANVPDD 88

                         90       100
                 ....*....|....*....|....*.
gi 740087244 119 TSLIPDSRDPQKVKE-FLQEKYEKKR 143
Cdd:cd08835   89 GSVKPTPDSSRQEREaWIRAKYVEKK 114

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 740087244  42 AGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPPH-RVKSISMTTFTEPEVLFLQSRGNEVCRKIWLGLFDARTS 120
Cdd:cd08849   13 TGNDVCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVHYsRMQSLTLDVLGTSELLLAKNIGNAGFNEIMEACLPAEDV 92

                         90       100
                 ....*....|....*....|....*
gi 740087244 121 LIPD-SRDPQKVKEFLQEKYEKKRW 144
Cdd:cd08849   93 VKPNpGSDMNARKDYITAKYIERRY 117

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 740087244  40 SQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPP-HRVKSISM--TTFTEPEVLFLQSRGNEVCRKIWLGLFD 116
Cdd:cd17901    9 SVESNRFCADCGSPKPDWASVNLCVVICKRCAGEHRGLGPSvSKVRSLKMdrKVWTEELIELFLLLGNGKANQFWAANVP 88

                         90       100
                 ....*....|....*....|....*...
gi 740087244 117 ARTSLIPDSrDPQKVKEFLQEKYEKKRW 144
Cdd:cd17901   89 PSEALCPSS-SSEERRHFITAKYKEGKY 115

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 740087244  40 SQAGNRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPPH-RVKSISMTTFTEPEVLFLQSRGNEVCRKIWLGLFDAR 118
Cdd:cd17900   11 SRPGNSQCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVRYsRIQSLTLDLLSTSELLLAVSMGNTRFNEVMEATLPAH 90

                         90       100
                 ....*....|....*....|....*..
gi 740087244 119 TSLIPDSR-DPQKVKEFLQEKYEKKRW 144
Cdd:cd17900   91 GGPKPSAEsDMGTRKDYIMAKYVEHRF 117

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 740087244  44 NRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPP-HRVKSISM--TTFTEPEVLFLQSRGNEVCRKIWLGLFDARTS 120
Cdd:cd08856   18 NRSCADCKAPDPDWASINLCVVICKKCAGQHRSLGPKdSKVRSLKMdaSIWSNELIELFIVVGNKPANLFWAANLFSEED 97

                         90       100
                 ....*....|....*....|....
gi 740087244 121 LIPDSrDPQKVKEFLQEKYEKKRW 144
Cdd:cd08856   98 LHMDS-DVEQRTPFITQKYKEGKF 120

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 740087244  44 NRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNPP-HRVKSISMTTFTEPEVLFLQSRGNEVCRKIW-LGLFDARTSL 121
Cdd:cd08833    8 ARVCADCSAPDPEWASINRGVLICDECCSIHRSLGRHiSQVKSLRKDQWPPSLLEMVQTLGNNGANSIWeHSLLDPSQSG 87

                         90       100
                 ....*....|....*....|...
gi 740087244 122 I-----PDSRDPQKvKEFLQEKY 139
Cdd:cd08833   88 KrkpipPDPVHPTK-EEFIKAKY 109

PPE-repeat protein [Function unknown];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244 188 SDPASTSSQPGSQSQARSSSQARSSQPPSHSSTKKASTDLLADIGGDPFAAPQVVPAFASFPGFGVGQTPAHGGFANFDA 267
Cdd:COG5651  168 TQPPPTITNPGGLLGAQNAGSGNTSSNPGFANLGLTGLNQVGIGGLNSGSGPIGLNSGPGNTGFAGTGAAAGAAAAAAAA 247

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 740087244 268 FSSSPSSSTFGSLPPSVQAPFQAQPTPAANRMLTGSYSFGSGQMSAFGVAPLAAASQPNNLADVGGLLGPRMAAGGLPGS 347
Cdd:COG5651  248 AAAAGAGASAALASLAATLLNASSLGLAATAASSAATNLGLAGSPLGLAGGGAGAAAATGLGLGAGGAAGAAGATGAGAA 327

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 740087244 348 VFGMPSqVPALQSAVPGVSGSGGLPFGAYTNPFATPAQAQLPSTNPFQPNGLASGPG 404
Cdd:COG5651  328 LGAGAA-AAAAGAAAGAGAAAAAAAGGAGGGGGGALGAGGGGGSAGAAAGAASGGGA 383