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 571465545  12 ERVIRGLLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREFTHRVKSVSMAKFTSQEVSALQEGGNQRAKEIYFK 91
Cdd:cd08838    1 EKILRELLKLPENKRCFDCGQRGPTYVNLTFGTFVCTTCSGIHREFNHRVKSISMSTFTPEEVEFLQAGGNEVARKIWLA 80

                         90       100       110
                 ....*....|....*....|....*....|.
gi 571465545  92 EWDAQRHSFPDSSNVDRLRDFIKHVYVDRRF 122
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 571465545    18 LLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHRE-FTHR--VKSVSMAKFTSQEVSALQEGGNQRAKEIYFKEWD 94
Cdd:smart00105   4 LRSIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSlGVHIskVRSLTLDTWTEEELRLLQKGGNENANSIWESNLD 83

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 571465545    95 AQRHSFPDSSNVDRLRDFIKHVYVDRRFTGDKTND 129
Cdd:smart00105  84 DFSLKPPDDDDQQKYESFIAAKYEEKLFVPPESAE 118

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 571465545  12 ERVIRGLLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREFTHRVKSVSMAKFTSQEVSALQEGGNQRAKEIYFK 91
Cdd:cd08838    1 EKILRELLKLPENKRCFDCGQRGPTYVNLTFGTFVCTTCSGIHREFNHRVKSISMSTFTPEEVEFLQAGGNEVARKIWLA 80

                         90       100       110
                 ....*....|....*....|....*....|.
gi 571465545  92 EWDAQRHSFPDSSNVDRLRDFIKHVYVDRRF 122
Cdd:cd08838   81 KWDPRTDPEPDSGDDQKIREFIRLKYVDKRW 111

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 571465545   12 ERVIRGLLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREF---THRVKSVSMAKFTSQEVSALQEGGNQRAKEI 88
Cdd:pfam01412   1 KRVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLgvhISKVRSLTLDTWTDEQLELMKAGGNDRANEF 80

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 571465545   89 YFKEWDAQrHSFPDSSNVDRLRDFIKHVYVDRRFT 123
Cdd:pfam01412  81 WEANLPPS-YKPPPSSDREKRESFIRAKYVEKKFA 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 571465545  18 LLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREF-TH--RVKSVSMAKFTSQEVSALQEGGNQRAKEIY-FKEW 93
Cdd:cd08204    4 LLKLPGNKVCADCGAPDPRWASINLGVFICIRCSGIHRSLgVHisKVRSLTLDSWTPEQVELMKAIGNARANAYYeANLP 83

                         90       100
                 ....*....|....*....|....
gi 571465545  94 DAQRHSFPDSSNVDRLRdFIKHVY 117
Cdd:cd08204   84 PGFKKPTPDSSDEEREQ-FIRAKY 106

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 571465545  24 NRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREFT--HRVKSVSMAKFTSQEVSALQEGGNQRAKEIYFKEWDAQRHSFP 101
Cdd:cd17903   14 NRHCFECAQRGVTYVDITVGSFVCTTCSGLLRGLNppHRVKSISMTTFTEPEVLFLQARGNEVCRKIWLGLFDARTSLIP 93

                         90       100
                 ....*....|....*....|.
gi 571465545 102 DSSNVDRLRDFIKHVYVDRRF 122
Cdd:cd17903   94 DSRDPQKVKEFLQEKYEKKRW 114

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 571465545  13 RVIRGLLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREF-THR--VKSVSMAKFTSQEVSALQEGGNQRAKEiY 89
Cdd:cd08830    3 AVLRELQKLPGNNRCFDCGAPNPQWASVSYGIFICLECSGVHRGLgVHIsfVRSITMDSWSEKQLKKMELGGNAKLRE-F 81

                 ...
gi 571465545  90 FKE 92
Cdd:cd08830   82 FES 84

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 571465545  14 VIRGLLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREF-TH--RVKSVSMAKFTSQEVSALQEGGNQRAKEiYF 90
Cdd:cd08831    5 IFKKLRSKPENKVCFDCGAKNPTWASVTFGVFLCLDCSGVHRSLgVHisFVRSTNLDSWTPEQLRRMKVGGNAKARE-FF 83

                         90
                 ....*....|....*.
gi 571465545  91 KEwdaqrHSFPDSSNV 106
Cdd:cd08831   84 KQ-----HGGLLSGDI 94

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 571465545  15 IRGLLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREF-TH--RVKSVSMAKFTSQEVSALQEGGNQRAKEIY 89
Cdd:cd08839    1 LAKLLREEDNKYCADCGAKGPRWASWNLGVFICIRCAGIHRNLgVHisKVKSVNLDSWTPEQVQSMQEMGNARANAYY 78

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 571465545  18 LLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREF-TH--RVKSVSMAKFTSQEVSALQEGGNQRAKEIY 89
Cdd:cd08859    4 LLLEEENKFCADCQSKGPRWASWNIGVFICIRCAGIHRNLgVHisRVKSVNLDQWTQEQIQCMQEMGNGKANRLY 78

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 571465545   9 EKNERVIRGLLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREFTH--RVKSVSMAKFTSQEVSALQEGGNQRAK 86
Cdd:cd08844    2 DRNKKRLLELLKLPGNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLPDisRVKSIRLDFWEDELVEFMKENGNLKAK 81

                 ...
gi 571465545  87 EIY 89
Cdd:cd08844   82 AKF 84

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 571465545  132 PRAKPGDKDDFYQGGSRSPPYEDTYErrynDRSSPGGRSPGYDQESRQYGDYKKSPGRP---PLINDWRREDRRTSDGDY 208
Cdd:PHA03247 2598 PRAPVDDRGDPRGPAPPSPLPPDTHA----PDPPPPSPSPAANEPDPHPPPTVPPPERPrddPAPGRVSRPRRARRLGRA 2673

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 571465545  209 KLESQSPERAKDvdSSSPPVVRPVRDiLGENVVPLRISEP------------PKPNSGR---PADSSAPTQRTISSSSLA 273
Cdd:PHA03247 2674 AQASSPPQRPRR--RAARPTVGSLTS-LADPPPPPPTPEPaphalvsatplpPGPAAARqasPALPAAPAPPAVPAGPAT 2750

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 571465545  274 SGNENPVDVKLETTKSlidfyADPEPPVAPSNLQAQQTTVPqPVVQPANSSNDNWASFDVAPATSATPSSSNLNPLESML 353
Cdd:PHA03247 2751 PGGPARPARPPTTAGP-----PAPAPPAAPAAGPPRRLTRP-AVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASP 2824

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 571465545  354 SQLSVPASLPAQVSGVQGPIPSSSLTSTSG-VASVSGFSAFPPSNASVPSPGLTSVSPLNNAGQWA---NLQQQKQPLFP 429
Cdd:PHA03247 2825 AGPLPPPTSAQPTAPPPPPGPPPPSLPLGGsVAPGGDVRRRPPSRSPAAKPAAPARPPVRRLARPAvsrSTESFALPPDQ 2904

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 571465545  430 AAVGQSIAQQFTPLLGGAANNQPWNVPSAPTvQGHPSTPMPHTypyaSKPANEAISSVVSQPPASEVKASGRKELPEDLF 509
Cdd:PHA03247 2905 PERPPQPQAPPPPQPQPQPPPPPQPQPPPPP-PPRPQPPLAPT----TDPAGAGEPSGAVPQPWLGALVPGRVAVPRFRV 2979

                         410
                  ....*....|
gi 571465545  510 TVKYSSFPAP 519
Cdd:PHA03247 2980 PQPAPSREAP 2989

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 571465545   9 EKNERVIRGLLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREFTH--RVKSVSMAKFTSQEVSALQEGGNQRAK 86
Cdd:cd08843    2 KERRRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQvsKVKSVRLDAWEEAQVEFMASHGNDAAR 81

                         90       100
                 ....*....|....*....|....*...
gi 571465545  87 EIYfkewDAQRHSF---PDSSNVDRLRD 111
Cdd:cd08843   82 ARF----ESKVPSFyyrPTPSDCQLLRE 105

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 571465545  12 ERVIRGLLKLQHNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREF-TH--RVKSVSMAKFTSQEVSALQEGGNQRAKEI 88
Cdd:cd08850    1 ESILQRVQSIAGNDQCCDCGQPDPRWASINLGILLCIECSGIHRSLgVHcsKVRSLTLDSWEPELLKLMCELGNSTVNQI 80

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 571465545  89 YFKEWDAQ--RHSFPDSSNVDRlRDFIKHVYVDRRF 122
Cdd:cd08850   81 YEAQCEELglKKPTASSSRQDK-EAWIKAKYVEKKF 115

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 3; 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. ARAP3 possesses a unique dual-specificity GAP activity for Arf6 and RhoA regulated by PI(3,4,5)P3 and a small GTPase Rap1-GTP. The RhoGAP activity of ARAP3 is enhanced by direct binding of Rap1-GTP to the Ras-association (RA) domain. ARAP3 is involved in regulation of cell shape and adhesion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 571465545  24 NRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREFTHRVKSVSMAK-----FTSQEVSALQEGGNQRAKEIYFKEWDAQRH 98
Cdd:cd17902   13 NRFCADCHASSPDWASINLCVVICKQCAGQHRSLGSGISKVQSLKldtsvWSNEIVQLFIVLGNDRANRFWAARLPASEA 92

                         90       100
                 ....*....|....*....|....
gi 571465545  99 SFPDSSNVDRlRDFIKHVYVDRRF 122
Cdd:cd17902   93 LHPDATPEQR-REFISRKYREGRF 115

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 571465545  24 NRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREF-TH--RVKSVSMAKFTSQEVSALQEGGNQRAKEIYFKEWDAQ--RH 98
Cdd:cd08852   13 NAQCCDCREPAPEWASINLGVTLCIQCSGIHRSLgVHfsKVRSLTLDSWEPELVKLMCELGNVIINQIYEARIEAMaiKK 92

                         90       100
                 ....*....|....*....|....
gi 571465545  99 SFPDSSNVDRlRDFIKHVYVDRRF 122
Cdd:cd08852   93 PGPSSSRQEK-EAWIRAKYVEKKF 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 571465545  13 RVIRGllklqhNRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREF-TH--RVKSVSMAKFTSQEVSALQEGGNQRAKEIY 89
Cdd:cd08855    9 RNVRG------NSFCIDCDAPNPDWASLNLGALMCIECSGIHRNLgTHlsRVRSLDLDDWPVELSMVMTAIGNAMANSVW 82

                         90       100
                 ....*....|....*....|.
gi 571465545  90 FKEWDAQRHSFPDSSNVDRLR 110
Cdd:cd08855   83 EGALDGYSKPGPDSTREEKER 103

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 571465545  24 NRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREF-TH--RVKSVSMAKFTSQEVSALQEGGNQRAKEIYfkewDAQRHSF 100
Cdd:cd08851   13 NASCCDCGLADPRWASINLGITLCIECSGIHRSLgVHfsKVRSLTLDTWEPELLKLMCELGNDVINRIY----EARVEKM 88

                         90       100
                 ....*....|....*....|....*..
gi 571465545 101 -----PDSSNVDRLRDFIKHVYVDRRF 122
Cdd:cd08851   89 gakkpQPGGQRQEKEAYIRAKYVERKF 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 571465545  24 NRRCINCNSLGPQYVCTNFWTFVCTNCSGIHREFTHRVKSVSMAKFTSQ----EVSALQEGGNQRAKEIY 89
Cdd:cd09029   19 NKACFDCGAKNPSWASITYGVFLCIDCSGVHRSLGVHLSFIRSTELDSNwnwfQLRCMQVGGNANATAFF 88

translocon at the inner envelope of chloroplast subunit 62; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 571465545 211 ESQSPERAKDVdSSSPPVVRPVRDILGENVVPLRISEPPKPNSGRPADSSAP--TQRTISSSSLASG--NENPVDVKLET 286
Cdd:PLN03209 356 IEEEPPQPKAV-VPRPLSPYTAYEDLKPPTSPIPTPPSSSPASSKSVDAVAKpaEPDVVPSPGSASNvpEVEPAQVEAKK 434

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 571465545 287 TKSLIDF--YADPEPPVAPSnlqaqqTTVPQPVVQPANSSNDNWASFDVAPATSATPSSSNLNPLESMLSQLSVPASLPa 364
Cdd:PLN03209 435 TRPLSPYarYEDLKPPTSPS------PTAPTGVSPSVSSTSSVPAVPDTAPATAATDAAAPPPANMRPLSPYAVYDDLK- 507