The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 2; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. ACAP2 (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 2), also called centaurin beta-2, is an Arf6-specific GTPase activating protein (GAP) which mediates Arf6 signaling. Arf6 is involved in the regulation of endocytosis, phagocytosis, cell adhesion and migration. ACAP2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  18 RAALEEVEGDVAELELKLDKLVKLCIAMIDTGKAFCVANKQFMNGIRDLAQYSSNDAVVETSLTKFSDSLQEMINFHTIL 97
Cdd:cd07638    1 RAALEDVEGDVAELELKLDKLVKLCIGMIDAGKAFCQANKQFMNGIRDLAQYSSKDAVIETSLTKFSDTLQEMINYHTIL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  98 FDQTQRSIKAQLQNFVKEDLRKFKDAKKQFEKVSEEKENALVKNAQVQRNKQHEVEEATNILTATRKCFRHIALDYVLQI 177
Cdd:cd07638   81 FDQAQRSIKAQLQTFVKEDLRKFKDAKKQFDKVSEEKENALVKNAQVQRNKQHEVEEATNILTATRKCFRHIALDYVLQI 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 187608516 178 NVLQSKRRSEILKSMLSFMYAHLAFFHQGYDLFSELGPYM 217
Cdd:cd07638  161 NVLQSKRRSEILKSMLSFMYAHLTFFHQGYDLFSELGPYM 200

ArfGAP with coiled-coil, ankyrin repeat and PH domains Pleckstrin homology (PH) domain; ACAP (also called centaurin beta) functions both as a Rab35 effector and as an Arf6-GTPase-activating protein (GAP) by which it controls actin remodeling and membrane trafficking. ACAP contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain, a phospholipid-binding domain, a PH domain, a GAP domain, and four ankyrin repeats. The AZAPs constitute a family of Arf GAPs that are characterized by an NH2-terminal pleckstrin homology (PH) domain and a central Arf GAP domain followed by two or more ankyrin repeats. On the basis of sequence and domain organization, the AZAP family is further subdivided into four subfamilies: 1) the ACAPs contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain (a phospholipid-binding domain that is thought to sense membrane curvature), a single PH domain followed by the GAP domain, and four ankyrin repeats; 2) the ASAPs also contain an NH2-terminal BAR domain, the tandem PH domain/GAP domain, three ankyrin repeats, two proline-rich regions, and a COOH-terminal Src homology 3 domain; 3) the AGAPs contain an NH2-terminal GTPase-like domain (GLD), a split PH domain, and the GAP domain followed by four ankyrin repeats; and 4) the ARAPs contain both an Arf GAP domain and a Rho GAP domain, as well as an NH2-terminal sterile-a motif (SAM), a proline-rich region, a GTPase-binding domain, and five PH domains. PMID 18003747 and 19055940 Centaurin can bind to phosphatidlyinositol (3,4,5)P3. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516 269 MEGYLFKRASNAFKTWNRRWFSIQNNQLVYQKKF-KDNPTVVVEDLRLCTVKHCEDIERRFCFEVVSPTKSCMLQADSEK 347
Cdd:cd13250    1 KEGYLFKRSSNAFKTWKRRWFSLQNGQLYYQKRDkKDEPTVMVEDLRLCTVKPTEDSDRRFCFEVISPTKSYMLQAESEE 80

                         90
                 ....*....|....*...
gi 187608516 348 LRQAWIKAVQTSIATAYR 365
Cdd:cd13250   81 DRQAWIQAIQSAIASALN 98

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 2; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. ACAP2 (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 2), also called centaurin beta-2, is an Arf6-specific GTPase activating protein (GAP) which mediates Arf6 signaling. Arf6 is involved in the regulation of endocytosis, phagocytosis, cell adhesion and migration. ACAP2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  18 RAALEEVEGDVAELELKLDKLVKLCIAMIDTGKAFCVANKQFMNGIRDLAQYSSNDAVVETSLTKFSDSLQEMINFHTIL 97
Cdd:cd07638    1 RAALEDVEGDVAELELKLDKLVKLCIGMIDAGKAFCQANKQFMNGIRDLAQYSSKDAVIETSLTKFSDTLQEMINYHTIL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  98 FDQTQRSIKAQLQNFVKEDLRKFKDAKKQFEKVSEEKENALVKNAQVQRNKQHEVEEATNILTATRKCFRHIALDYVLQI 177
Cdd:cd07638   81 FDQAQRSIKAQLQTFVKEDLRKFKDAKKQFDKVSEEKENALVKNAQVQRNKQHEVEEATNILTATRKCFRHIALDYVLQI 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 187608516 178 NVLQSKRRSEILKSMLSFMYAHLAFFHQGYDLFSELGPYM 217
Cdd:cd07638  161 NVLQSKRRSEILKSMLSFMYAHLTFFHQGYDLFSELGPYM 200

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 187608516 399 ESALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRV 478
Cdd:cd08851    1 ESALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRI 80

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 187608516 479 YEANVEKMGIKKPQPG-QRQEKEAYIRAKYVERKFV 513
Cdd:cd08851   81 YEARVEKMGAKKPQPGgQRQEKEAYIRAKYVERKFV 116

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 187608516   402 LQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEA 481
Cdd:smart00105   1 LKLLRSIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSLGVHISKVRSLTLDTWTEEELRLLQKGGNENANSIWES 80

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 187608516   482 NVEKMGIKKPQPGQRQEKEAYIRAKYVERKFVDKYS 517
Cdd:smart00105  81 NLDDFSLKPPDDDDQQKYESFIAAKYEEKLFVPPES 116

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 187608516 387 SGNESKEKLLKgesALQRvqcIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKL 466
Cdd:COG5347    2 STKSEDRKLLK---LLKS---DSSNKKCADCGAPNPTWASVNLGVFLCIDCAGVHRSLGVHISKVKSLTLDNWTEEELRR 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516 467 MCELGNDVINRVYEANvekmGIKKPQPGQR-----QEKEAYIRAKYVERKFVD---KYSISLSPPEQQKKFVSKSSEEKR 538
Cdd:COG5347   76 MEVGGNSNANRFYEKN----LLDQLLLPIKakydsSVAKKYIRKKYELKKFIDdssSPSDFSSFSASSTRTVDSVDDRLD 151

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|.
gi 187608516 539 LSISKFGPGDQVRASAQSSVRSNDSGIQQSSDDGRESLPST 579
Cdd:COG5347  152 SESQSRSSSASLGNSNRPDDELNVESFQSTGSKPRSLTSTK 192

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516   267 IVMEGYLFKRASNAFKTWNRRWFSIQNNQLVYQKKFKDNPTVVVE---DLRLCTVKHCEDI---ERRFCFEVVSPTKSCM 340
Cdd:smart00233   1 VIKEGWLYKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYKPKgsiDLSGCTVREAPDPdssKKPHCFEIKTSDRKTL 80

                           90       100
                   ....*....|....*....|..
gi 187608516   341 -LQADSEKLRQAWIKAVQTSIA 361
Cdd:smart00233  81 lLQAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  267 IVMEGYLFKRASNAFKTWNRRWFSIQNNQLVYQK----KFKDNPTVVVeDLRLCTVKHCEDIE---RRFCFEVVSPTKSC 339
Cdd:pfam00169   1 VVKEGWLLKKGGGKKKSWKKRYFVLFDGSLLYYKddksGKSKEPKGSI-SLSGCEVVEVVASDspkRKFCFELRTGERTG 79

                          90       100
                  ....*....|....*....|....*.
gi 187608516  340 M----LQADSEKLRQAWIKAVQTSIA 361
Cdd:pfam00169  80 KrtylLQAESEEERKDWIKAIQSAIR 105

Ankyrin repeats (3 copies);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  645 LIQAVLGGSLVTCEFLLQNGANVNQRDVQGRGPLHHATVLGHTgQVCLFLKRGANQHATDeEGKDPLSIAVEAANADIVT 724
Cdd:pfam12796   1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHL-EIVKLLLEHADVNLKD-NGRTALHYAARSGHLEIVK 78

                  ..
gi 187608516  725 LL 726
Cdd:pfam12796  79 LL 80

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 2; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. ACAP2 (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 2), also called centaurin beta-2, is an Arf6-specific GTPase activating protein (GAP) which mediates Arf6 signaling. Arf6 is involved in the regulation of endocytosis, phagocytosis, cell adhesion and migration. ACAP2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  18 RAALEEVEGDVAELELKLDKLVKLCIAMIDTGKAFCVANKQFMNGIRDLAQYSSNDAVVETSLTKFSDSLQEMINFHTIL 97
Cdd:cd07638    1 RAALEDVEGDVAELELKLDKLVKLCIGMIDAGKAFCQANKQFMNGIRDLAQYSSKDAVIETSLTKFSDTLQEMINYHTIL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  98 FDQTQRSIKAQLQNFVKEDLRKFKDAKKQFEKVSEEKENALVKNAQVQRNKQHEVEEATNILTATRKCFRHIALDYVLQI 177
Cdd:cd07638   81 FDQAQRSIKAQLQTFVKEDLRKFKDAKKQFDKVSEEKENALVKNAQVQRNKQHEVEEATNILTATRKCFRHIALDYVLQI 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 187608516 178 NVLQSKRRSEILKSMLSFMYAHLAFFHQGYDLFSELGPYM 217
Cdd:cd07638  161 NVLQSKRRSEILKSMLSFMYAHLTFFHQGYDLFSELGPYM 200

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing proteins; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. This subfamily is composed of ACAPs (ArfGAP with Coiled-coil, ANK repeat and PH domain containing proteins), which are Arf GTPase activating proteins (GAPs) containing an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. Vertebrates contain at least three members, ACAP1, ACAP2, and ACAP3. ACAP1 and ACAP2 are Arf6-specific GAPs, involved in the regulation of endocytosis, phagocytosis, cell adhesion and migration, by mediating Arf6 signaling. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  18 RAALEEVEGDVAELELKLDKLVKLCIAMIDTGKAFCVANKQFMNGIRDLAQYSSNDAVVETSLTKFSDSLQEMINFHTIL 97
Cdd:cd07603    1 RASLEQVEADVSELETRLEKLLKLCNGMVDSGKTYVNANSLFVNSLNDLSDYFRDDSLVQNCLNKFIQALQEMNNFHTIL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  98 FDQTQRSIKAQLQNFVKEDLRKFKDAKKQFEKVSEEKENALVKNAQVQRNKQHEVEEATNILTATRKCFRHIALDYVLQI 177
Cdd:cd07603   81 LDQAQRTVSTQLQNFVKEDIKKVKESKKHFEKISDDLDNALVKNAQAPRSKPQEAEEATNILTATRSCFRHTALDYVLQI 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 187608516 178 NVLQSKRRSEILKSMLSFMYAHLAFFHQGYDLFSELGPYM 217
Cdd:cd07603  161 NVLQAKKRHEILSTLLSYMHAQFTFFHQGYDLLEDLEPYM 200

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 187608516 399 ESALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRV 478
Cdd:cd08851    1 ESALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRI 80

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 187608516 479 YEANVEKMGIKKPQPG-QRQEKEAYIRAKYVERKFV 513
Cdd:cd08851   81 YEARVEKMGAKKPQPGgQRQEKEAYIRAKYVERKFV 116

ArfGAP domain of ACAP3 (ArfGAP with Coiled-coil, ANK repeat and PH domains 3); ACAP3 belongs to the ACAP subfamily of GAPs (GTPase-activating proteins) for the small GTPase Arf (ADP-ribosylation factor). ACAP subfamily of ArfGAPs are composed of Coiled coli (BAR, Bin-Amphiphysin-Rvs), PH, ArfGAP and ANK repeats domains. It has been shown that ACAP3 positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) also have a GAP (GTPase-activating protein) activity preferentially toward Arf6, which regulates endocytic recycling. Both ACAP1/2 are activated by are activated by the phosphoinositides, PI(4,5)P2 and PI(3,5)P2. ACAP1 binds specifically with recycling cargo proteins such as transferrin receptor (TfR) and cellubrevin. Thus, ACAP1 promotes cargo sorting to enhance TfR recycling from the recycling endosome. In addition, phosphorylation of ACAP by Akt, a serine/threonine protein kinase, regulates the recycling of integrin beta1 to control cell migration. In contrast, ACAP2 does not exhibit a similar interaction with the recycling cargo proteins. It has been shown that ACAP2 functions both as an effector of Ras-related protein Rab35 and as an Arf6-GTPase-activating protein (GAP) during neurite outgrowth of PC12 cells. Moreover, ACAP2, together with Rab35, regulates phagocytosis in mammalian macrophages.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516 399 ESALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRV 478
Cdd:cd08850    1 ESILQRVQSIAGNDQCCDCGQPDPRWASINLGILLCIECSGIHRSLGVHCSKVRSLTLDSWEPELLKLMCELGNSTVNQI 80

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 187608516 479 YEANVEKMGIKKPQPG-QRQEKEAYIRAKYVERKFV 513
Cdd:cd08850   81 YEAQCEELGLKKPTASsSRQDKEAWIKAKYVEKKFL 116

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 1; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. ACAP1 (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 1), also called centaurin beta-1, is an Arf6-specific GTPase activating protein (GAP) which mediates Arf6 signaling. Arf6 is involved in the regulation of endocytosis, phagocytosis, cell adhesion and migration. ACAP1 also participates in the cargo sorting and recycling of the transferrin receptor and integrin beta1. It may also play a role in innate immune responses. ACAP1 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  18 RAALEEVEGDVAELELKLDKLVKLCIAMIDTGKAFCVANKQFMNGIRDLAQYSSNDAVVETSLTKFSDSLQEMINFHTIL 97
Cdd:cd07639    1 RAAIEEVEAEVSELETRLEKLVKLGSGMLEGGRHYCAASRAFVDGLCDLAHHGPKDPMMAECLEKFSDGLNHILDSHAEL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516  98 FDQTQRSIKAQLQNFVKEDLRKFKDAKKQFEKVSEEKENALVKNAQVQRNKQHEVEEATNILTATRKCFRHIALDYVLQI 177
Cdd:cd07639   81 LEATQFSFKQQLQLLVKEDLRGFRDARKEFERGAESLEAALQHNAETPRRKAQEVEEAAAALLGARATFRDRALDYALQI 160

                        170       180       190
                 ....*....|....*....|....*....|....*....
gi 187608516 178 NVLQSKRRSEILKSMLSFMYAHLAFFHQGYDLFSELGPY 216
Cdd:cd07639  161 NVIEDKKKFDILEFMLQLMEAQASFFQQGHEALSALHQY 199

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 187608516 402 LQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEA 481
Cdd:cd08204    1 LEELLKLPGNKVCADCGAPDPRWASINLGVFICIRCSGIHRSLGVHISKVRSLTLDSWTPEQVELMKAIGNARANAYYEA 80

                         90       100
                 ....*....|....*....|....*..
gi 187608516 482 NVEKmGIKKPQPGQ-RQEKEAYIRAKY 507
Cdd:cd08204   81 NLPP-GFKKPTPDSsDEEREQFIRAKY 106

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 187608516  399 ESALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRV 478
Cdd:pfam01412   1 KRVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLGVHISKVRSLTLDTWTDEQLELMKAGGNDRANEF 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 187608516  479 YEANVEKmGIKKPQPGQRQEKEAYIRAKYVERKFVDK 515
Cdd:pfam01412  81 WEANLPP-SYKPPPSSDREKRESFIRAKYVEKKFAKP 116

ArfGAP domain of ASAP (Arf GAP, SH3, ANK repeat and PH domains) subfamily of ADP-ribosylation factor GTPase-activating proteins; The ArfGAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP3, ASAP1 and ASAP2 also have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport. ASAP3 is a focal adhesion-associated ArfGAP that functions in cell migration and invasion. Similar to ASAP1, the GAP activity of ASAP3 is strongly enhanced by PIP2 via PH domain. Like ASAP1, ASAP3 associates with focal adhesions and circular dorsal ruffles. However, unlike ASAP1, ASAP3 does not localize to invadopodia or podosomes. Both ASAP 1 and 3 have been implicated in oncogenesis, as ASAP1 is highly expressed in metastatic breast cancer and ASAP3 in hepatocellular carcinoma.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516 400 SALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVY 479
Cdd:cd08834    4 SIIAEVKRLPGNDVCCDCGSPDPTWLSTNLGILTCIECSGVHRELGVHVSRIQSLTLDNLGTSELLLARNLGNEGFNEIM 83

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 187608516 480 EANVEkmGIKKPQPG-QRQEKEAYIRAKYVERKFV 513
Cdd:cd08834   84 EANLP--PGYKPTPNsDMEERKDFIRAKYVEKKFV 116

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 187608516 409 PGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEANVEKmGI 488
Cdd:cd08839    8 EDNKYCADCGAKGPRWASWNLGVFICIRCAGIHRNLGVHISKVKSVNLDSWTPEQVQSMQEMGNARANAYYEANLPD-GF 86

                         90
                 ....*....|....*....
gi 187608516 489 KKPQPgqRQEKEAYIRAKY 507
Cdd:cd08839   87 RRPQT--DSALENFIRDKY 103

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 187608516 405 VQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEANVE 484
Cdd:cd17900    9 VKSRPGNSQCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVRYSRIQSLTLDLLSTSELLLAVSMGNTRFNEVMEATLP 88

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 187608516 485 KMGIKKPQP----GQRQEkeaYIRAKYVERKFVDK 515
Cdd:cd17900   89 AHGGPKPSAesdmGTRKD---YIMAKYVEHRFVRK 120

ArfGAP with GTPase domain, ANK repeat and PH domain 1; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516 401 ALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYE 480
Cdd:cd08854    3 AIQAIRNAKGNSLCVDCGAPNPTWASLNLGALICIECSGIHRNLGTHLSRVRSLDLDDWPRELTLVLTAIGNHMANSIWE 82

                         90       100
                 ....*....|....*....|....*...
gi 187608516 481 ANVEkmGIKKPQP-GQRQEKEAYIRAKY 507
Cdd:cd08854   83 SCTQ--GRTKPAPdSSREERESWIRAKY 108

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 187608516 402 LQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEA 481
Cdd:cd08849    6 ISEVQRMTGNDVCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVHYSRMQSLTLDVLGTSELLLAKNIGNAGFNEIMEA 85

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 187608516 482 NVEKMGIKKPQPGQ-RQEKEAYIRAKYVERKFVDK 515
Cdd:cd08849   86 CLPAEDVVKPNPGSdMNARKDYITAKYIERRYARK 120

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 187608516 399 ESALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRV 478
Cdd:cd08848    3 KAIIDDVQRLPGNEVCCDCGSPDPTWLSTNLGILTCIECSGIHREMGVHISRIQSLELDKLGTSELLLAKNVGNNSFNDI 82

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 187608516 479 YEANVEKMGIKKPQPGQRQEKEAYIRAKYVERKFVDK 515
Cdd:cd08848   83 MEGNLPSPSPKPSPSSDMTARKEYITAKYVEHRFSRK 119

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 187608516 402 LQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGND 473
Cdd:cd08830    5 LRELQKLPGNNRCFDCGAPNPQWASVSYGIFICLECSGVHRGLGVHISFVRSITMDSWSEKQLKKMELGGNA 76

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187608516 411 NASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEANVEKmGIKK 490
Cdd:cd08859   10 NKFCADCQSKGPRWASWNIGVFICIRCAGIHRNLGVHISRVKSVNLDQWTQEQIQCMQEMGNGKANRLYEAFLPE-NFRR 88

                         90       100
                 ....*....|....*....|.
gi 187608516 491 PQpgQRQEKEAYIRAKYVERK 511
Cdd:cd08859   89 PQ--TDQAVEGFIRDKYEKKK 107

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 187608516 402 LQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGND 473
Cdd:cd08831    6 FKKLRSKPENKVCFDCGAKNPTWASVTFGVFLCLDCSGVHRSLGVHISFVRSTNLDSWTPEQLRRMKVGGNA 77

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 187608516 402 LQRvqciPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGvHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEA 481
Cdd:cd08843   12 LQR----PGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIP-QVSKVKSVRLDAWEEAQVEFMASHGNDAARARFES 86

                         90       100
                 ....*....|....*....|....*..
gi 187608516 482 NVEKMgIKKPQPGQRQ-EKEAYIRAKY 507
Cdd:cd08843   87 KVPSF-YYRPTPSDCQlLREQWIRAKY 112