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 1519316057   2 AKERRRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQVSKVKSVRLDAWEEAQVEFMASHGNDAA 81
Cdd:cd08843     1 GKERRRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQVSKVKSVRLDAWEEAQVEFMASHGNDAA 80

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1519316057  82 RARFESKVPSFYYRPTPSDCQLLREQWIRAKY 113
Cdd:cd08843    81 RARFESKVPSFYYRPTPSDCQLLREQWIRAKY 112

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 2; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the second PH domain repeat. 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 1519316057 252 NYLKEGYMEKTGPKQTEGFRKRWFTMDDRRLMYFKDPLDAFARGEVFIGSKESGYTVLHGFPPSTQGhHWPHGITIVTPD 331
Cdd:cd01251     1 DFLKEGYLEKTGPKQTDGFRKRWFTLDDRRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVTPD 79

                          90       100
                  ....*....|....*....|....*.
gi 1519316057 332 RKFLFACETESDQREWVAAFQKAVDR 357
Cdd:cd01251    80 RTFLLSAETEEERREWITAIQKVLER 105

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 1519316057   2 AKERRRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQVSKVKSVRLDAWEEAQVEFMASHGNDAA 81
Cdd:cd08843     1 GKERRRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQVSKVKSVRLDAWEEAQVEFMASHGNDAA 80

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1519316057  82 RARFESKVPSFYYRPTPSDCQLLREQWIRAKY 113
Cdd:cd08843    81 RARFESKVPSFYYRPTPSDCQLLREQWIRAKY 112

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 2; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the second PH domain repeat. 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 1519316057 252 NYLKEGYMEKTGPKQTEGFRKRWFTMDDRRLMYFKDPLDAFARGEVFIGSKESGYTVLHGFPPSTQGhHWPHGITIVTPD 331
Cdd:cd01251     1 DFLKEGYLEKTGPKQTDGFRKRWFTLDDRRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVTPD 79

                          90       100
                  ....*....|....*....|....*.
gi 1519316057 332 RKFLFACETESDQREWVAAFQKAVDR 357
Cdd:cd01251    80 RTFLLSAETEEERREWITAIQKVLER 105

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 1519316057   6 RRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNI-PQVSKVKSVRLDAWEEAQVEFMASHGNDAARAR 84
Cdd:pfam01412   1 KRVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLgVHISKVRSLTLDTWTDEQLELMKAGGNDRANEF 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1519316057  85 FESKVPSFYYRPtPSDCQLLREQWIRAKYERQEFIYPE 122
Cdd:pfam01412  81 WEANLPPSYKPP-PSSDREKRESFIRAKYVEKKFAKPG 117

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 1519316057  254 LKEGYMEKTGPKQTEGFRKRWFTMDDRRLMYFKDP---LDAFARGEVFIgskeSGYTVLHgfPPSTQGHHWPHGITIVTP 330
Cdd:smart00233   2 IKEGWLYKKSGGGKKSWKKRYFVLFNSTLLYYKSKkdkKSYKPKGSIDL----SGCTVRE--APDPDSSKKPHCFEIKTS 75

                           90       100
                   ....*....|....*....|....*..
gi 1519316057  331 DRK-FLFACETESDQREWVAAFQKAVD 356
Cdd:smart00233  76 DRKtLLLQAESEEEREKWVEALRKAIA 102

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1519316057  11 ELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIP-QVSKVKSVRLDAWEEAQVEFMASHGNDAARARFE 86
Cdd:PLN03114   15 KLKAKSDNKICFDCNAKNPTWASVTYGIFLCIDCSAVHRSLGvHISFVRSTNLDSWSSEQLKMMIYGGNNRAQVFFK 91

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 1519316057  131 YREGFLWKRGRD-NGQFLSRKFVLteREGALKYF-NRNDAKEPKAVMKIEHLNATFQPA----KIGHPHGLQVTYlkdNS 204
Cdd:smart00233   2 IKEGWLYKKSGGgKKSWKKRYFVL--FNSTLLYYkSKKDKKSYKPKGSIDLSGCTVREApdpdSSKKPHCFEIKT---SD 76

                           90       100
                   ....*....|....*....|....
gi 1519316057  205 TRNIFIYHEDGKEIVDWFNALRAA 228
Cdd:smart00233  77 RKTLLLQAESEEEREKWVEALRKA 100

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 1519316057   2 AKERRRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQVSKVKSVRLDAWEEAQVEFMASHGNDAA 81
Cdd:cd08843     1 GKERRRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQVSKVKSVRLDAWEEAQVEFMASHGNDAA 80

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1519316057  82 RARFESKVPSFYYRPTPSDCQLLREQWIRAKY 113
Cdd:cd08843    81 RARFESKVPSFYYRPTPSDCQLLREQWIRAKY 112

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 1; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the first PH domain repeat. 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 1519316057 130 GYREGFLWKRGRDNGQFLSRKFVLTEREGALKYFNRNDAKEPKAVMKIEHLNATFQPAKIGHPHGLQVTYLKDNSTRNIF 209
Cdd:cd13252     1 GSKEGFLWKRGKDNNQFKQRKFVLSEREGTLKYFVKEDAKEPKAVISIEELNATFQPEKIGHPNGLQITYLKDGSTRNIF 80

                          90       100
                  ....*....|....*....|....*....
gi 1519316057 210 IYHEDGKEIVDWFNALRAARFHYLQVAFP 238
Cdd:cd13252    81 VYHEDGKEIVDWYNAIRAARLHYLQVAFP 109

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 1519316057   4 ERRRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQVSKVKSVRLDAWEEAQVEFMASHGNDAARA 83
Cdd:cd08844     3 RNKKRLLELLKLPGNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLPDISRVKSIRLDFWEDELVEFMKENGNLKAKA 82

                          90       100       110
                  ....*....|....*....|....*....|
gi 1519316057  84 RFESKVPSFYYRPTPSDCQLLREQWIRAKY 113
Cdd:cd08844    83 KFEAFVPPFYYRPQANDCDVLKEQWIRAKY 112

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 1519316057   10 LELLQR-PGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNI-PQVSKVKSVRLDAWEEAQVEFMASHGNDAARARFES 87
Cdd:smart00105   1 LKLLRSiPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSLgVHISKVRSLTLDTWTEEELRLLQKGGNENANSIWES 80

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 1519316057   88 KVPSFYYRPTPSDCQLLREQWIRAKYERQEFIYPEKQEP 126
Cdd:smart00105  81 NLDDFSLKPPDDDDQQKYESFIAAKYEEKLFVPPESAEE 119

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 1519316057  11 ELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNI-PQVSKVKSVRLDAWEEAQVEFMASHGNDAARARFESKV 89
Cdd:cd08839     3 KLLREEDNKYCADCGAKGPRWASWNLGVFICIRCAGIHRNLgVHISKVKSVNLDSWTPEQVQSMQEMGNARANAYYEANL 82

                          90       100
                  ....*....|....*....|....
gi 1519316057  90 PSFYYRPtPSDCQLlrEQWIRAKY 113
Cdd:cd08839    83 PDGFRRP-QTDSAL--ENFIRDKY 103

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 1519316057   8 AVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNI-PQVSKVKSVRLDAWEEAQVEFMASHGNDAARARFE 86
Cdd:cd08836     2 ALQAIRNVRGNDHCVDCGAPNPDWASLNLGALMCIECSGIHRNLgTHISRVRSLDLDDWPVELLKVMSAIGNDLANSVWE 81

                          90       100
                  ....*....|....*....|....*...
gi 1519316057  87 SKVPSfYYRPTPSDCQLLREQWIRAKYE 114
Cdd:cd08836    82 GNTQG-RTKPTPDSSREEKERWIRAKYE 108

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 1519316057   2 AKERRRAVLELLQR-PGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNI-PQVSKVKSVRLDAWEEAQVEFMASHGND 79
Cdd:COG5347     3 TKSEDRKLLKLLKSdSSNKKCADCGAPNPTWASVNLGVFLCIDCAGVHRSLgVHISKVKSLTLDNWTEEELRRMEVGGNS 82

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1519316057  80 AARARFESK---VPSFYYRPTPSDcqLLREQWIRAKYERQEFIY 120
Cdd:COG5347    83 NANRFYEKNlldQLLLPIKAKYDS--SVAKKYIRKKYELKKFID 124

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 1519316057  12 LLQR----PGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIP-QVSKVKSVRLDAWEEAQVEFMASHGNDAARARFE 86
Cdd:cd08850     3 ILQRvqsiAGNDQCCDCGQPDPRWASINLGILLCIECSGIHRSLGvHCSKVRSLTLDSWEPELLKLMCELGNSTVNQIYE 82

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1519316057  87 SKVPSFYYR-PTPSDCQLLREQWIRAKYERQEFI 119
Cdd:cd08850    83 AQCEELGLKkPTASSSRQDKEAWIKAKYVEKKFL 116

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 1519316057   4 ERRRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNI-PQVSKVKSVRLDAWEEAQVEFMASHGNDAAR 82
Cdd:cd08831     1 ERDAIFKKLRSKPENKVCFDCGAKNPTWASVTFGVFLCLDCSGVHRSLgVHISFVRSTNLDSWTPEQLRRMKVGGNAKAR 80

                  ....*
gi 1519316057  83 ARFES 87
Cdd:cd08831    81 EFFKQ 85

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 1519316057  11 ELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIP-QVSKVKSVRLDAWEEAQVEFMASHGNDAARARFESKV 89
Cdd:cd08859     3 SLLLEEENKFCADCQSKGPRWASWNIGVFICIRCAGIHRNLGvHISRVKSVNLDQWTQEQIQCMQEMGNGKANRLYEAFL 82

                          90       100
                  ....*....|....*....|....*...
gi 1519316057  90 PSFYYRPTpSDCQLlrEQWIRAKYERQE 117
Cdd:cd08859    83 PENFRRPQ-TDQAV--EGFIRDKYEKKK 107

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 1519316057  17 GNARCADCGAPDPDWASYTLGVFICLSCSGIHRNI-PQVSKVKSVRLDAWEEAQVEFMASHGNDAARARFESKVPSfYYR 95
Cdd:cd08854    12 GNSLCVDCGAPNPTWASLNLGALICIECSGIHRNLgTHLSRVRSLDLDDWPRELTLVLTAIGNHMANSIWESCTQG-RTK 90

                          90
                  ....*....|....*....
gi 1519316057  96 PTPSDCQLLREQWIRAKYE 114
Cdd:cd08854    91 PAPDSSREERESWIRAKYE 109

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 1519316057   6 RRAVLELLQR-PGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIP-QVSKVKSVRLDAWEEAQVEFMASHGNDAARA 83
Cdd:cd08834     2 TKSIIAEVKRlPGNDVCCDCGSPDPTWLSTNLGILTCIECSGVHRELGvHVSRIQSLTLDNLGTSELLLARNLGNEGFNE 81

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1519316057  84 RFESKVPSfYYRPTPSDCQLLREQWIRAKYERQEFI 119
Cdd:cd08834    82 IMEANLPP-GYKPTPNSDMEERKDFIRAKYVEKKFV 116

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 1519316057   7 RAVLELLQR-PGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIP-QVSKVKSVRLDAWEEAQVEFMASHGNDAARAR 84
Cdd:cd08848     3 KAIIDDVQRlPGNEVCCDCGSPDPTWLSTNLGILTCIECSGIHREMGvHISRIQSLELDKLGTSELLLAKNVGNNSFNDI 82

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1519316057  85 FESKVPSFYYRPTPSDCQLLREQWIRAKYERQEF 118
Cdd:cd08848    83 MEGNLPSPSPKPSPSSDMTARKEYITAKYVEHRF 116

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 1519316057  15 RPGNAR-CADCGAPDPDWASYTLGVFICLSCSGIHRNI-PQVSKVKSVRLDAWEEAQVEFMASHGNDAARARFESKVP-- 90
Cdd:cd08833     4 KSSNARvCADCSAPDPEWASINRGVLICDECCSIHRSLgRHISQVKSLRKDQWPPSLLEMVQTLGNNGANSIWEHSLLdp 83

                          90       100
                  ....*....|....*....|....*.
gi 1519316057  91 --SFYYRPTPSDCQL-LREQWIRAKY 113
Cdd:cd08833    84 sqSGKRKPIPPDPVHpTKEEFIKAKY 109

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 1519316057  16 PGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNI-PQVSKVKSVRLD--AWEEAQVEFMASHGNDAARARFESKVPsf 92
Cdd:cd17901    11 ESNRFCADCGSPKPDWASVNLCVVICKRCAGEHRGLgPSVSKVRSLKMDrkVWTEELIELFLLLGNGKANQFWAANVP-- 88

                          90       100
                  ....*....|....*....|....*
gi 1519316057  93 yyrPT----PSDCQLLREQWIRAKY 113
Cdd:cd17901    89 ---PSealcPSSSSEERRHFITAKY 110

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 1519316057   7 RAVLELLQR-PGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIP-QVSKVKSVRLDAWEEAQVEFMASHGNDAARAR 84
Cdd:cd08849     3 KEIISEVQRmTGNDVCCDCGAPDPTWLSTNLGILTCIECSGIHRELGvHYSRMQSLTLDVLGTSELLLAKNIGNAGFNEI 82

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1519316057  85 FESKVPSF-YYRPTPSDCQLLREQWIRAKYERQEF 118
Cdd:cd08849    83 MEACLPAEdVVKPNPGSDMNARKDYITAKYIERRY 117

Arf1 GTPase-activating protein 2; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1519316057   4 ERRRAVlellqrPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIP-QVSKVKSVRLDA-WEEAQVEFMASHGNDAA 81
Cdd:cd09029    11 KRLRAI------PTNKACFDCGAKNPSWASITYGVFLCIDCSGVHRSLGvHLSFIRSTELDSnWNWFQLRCMQVGGNANA 84

                  ....
gi 1519316057  82 RARF 85
Cdd:cd09029    85 TAFF 88

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1519316057 255 KEGYMEKTGPKQTEGFRKRWFTMDDRRLMYFKDPL---DAFARGEVFIgskeSGYTVLHGFPPSTQGHHWPHGITIV--T 329
Cdd:pfam00169   3 KEGWLLKKGGGKKKSWKKRYFVLFDGSLLYYKDDKsgkSKEPKGSISL----SGCEVVEVVASDSPKRKFCFELRTGerT 78

                          90       100
                  ....*....|....*....|....*.
gi 1519316057 330 PDRKFLFACETESDQREWVAAFQKAV 355
Cdd:pfam00169  79 GKRTYLLQAESEEERKDWIKAIQSAI 104

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1519316057  11 ELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIP-QVSKVKSVRLDAWEEAQVEFMASHGNDAARARFE 86
Cdd:PLN03114   15 KLKAKSDNKICFDCNAKNPTWASVTYGIFLCIDCSAVHRSLGvHISFVRSTNLDSWSSEQLKMMIYGGNNRAQVFFK 91

ArfGAP domain of AGFG1 (ArfGAP domain and FG repeat-containing protein 1); The ArfGAP domain and FG repeat-containing proteins (AFGF) subfamily of Arf GTPase-activating proteins consists of the two structurally-related members: AGFG1 and AGFG2. AGFG1 (alias: HIV-1 Rev binding protein, HRB; Rev interacting protein, RIP; Rev/Rex activating domain-binding protein, RAB) and AGFG2 are involved in the maintenance and spread of immunodeficiency virus type 1 (HIV-1) infection. The ArfGAP domain of AGFG1 is related to nucleoporins, which is a class of proteins that mediate nucleocytoplasmic transport. AGFG1 plays a role in the Rev export pathway, which mediates the nucleocytoplasmic transfer of proteins and RNAs, possibly together by the nuclear export receptor CRM1. In humans, the presence of the FG repeat motifs (11 in AGFG1 and 7 in AGFG2) are thought to be required for these proteins to act as HIV-1 Rev cofactors. Hence, AGFG1 promotes movement of Rev-responsive element-containing RNAs from the nuclear periphery to the cytoplasm, which is an essential step for HIV-1 replication.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1519316057  11 ELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQVSKVKSVRLDAWEEAQVEFMASHGNDAARARF----- 85
Cdd:cd08857     7 EMTSLPHNRKCFDCDQRGPTYANMTVGSFVCTSCSGILRGLNPPHRVKSISMTTFTQQEIEFLQKHGNEVCKQIWlglfd 86

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1519316057  86 --ESKVPSFyyrptpSDCQLLREqWIRAKYERQEF 118
Cdd:cd08857    87 drSSAIPDF------RDPQKVKE-FLQEKYEKKRW 114

GIT1 GTPase activating protein for Arf; 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 1519316057  21 CADCGAPDPDWASYTLGVFICLSCSGIHRNIPQ-VSKVKSVRLDAWEEAQVEFMASHGNDAARARFE------SKVPSFY 93
Cdd:cd08846    11 CADCSAPDPGWASINRGVLICDECCSVHRSLGRhISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEhslldpAQVQSGR 90

                          90       100
                  ....*....|....*....|.
gi 1519316057  94 YRPTPSD-CQLLREQWIRAKY 113
Cdd:cd08846    91 RKANPQDkVHPTKSEFIRAKY 111

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 1; ARAP proteins (also called centaurin delta) are phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating proteins that modulate actin cytoskeleton remodeling by regulating ARF and RHO family members. They bind phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4,5)P2) binding. There are 3 mammalian ARAP proteins: ARAP1, ARAP2, and ARAP3. All ARAP proteins contain a N-terminal SAM (sterile alpha motif) domain, 5 PH domains, an ArfGAP domain, 2 ankyrin domain, A RhoGap domain, and a Ras-associating domain. This hierarchy contains the first PH domain in ARAP. 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 1519316057 254 LKEGYMEKTGPKQTE-GFRKRWFTMDDRRLMYFKDPLDAFARGEVfigskesgytvlhgfpPSTQGHHWP----HGITIV 328
Cdd:cd13253     1 IKSGYLDKQGGQGNNkGFQKRWVVFDGLSLRYFDSEKDAYSKRII----------------PLSAISTVRavgdNKFELV 64

                          90       100
                  ....*....|....*....|....*..
gi 1519316057 329 TPDRKFLFACETESDQREWVAAFQKAV 355
Cdd:cd13253    65 TTNRTFVFRAESDDERNLWCSTLQAAI 91

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1519316057   3 KERRRAVLE-LLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQvsKVKSVRLDAWEEAQVEFMASHGNDAA 81
Cdd:PLN03119    7 EERNEKIIRgLMKLPPNRRCINCNSLGPQYVCTTFWTFVCMACSGIHREFTH--RVKSVSMSKFTSKEVEVLQNGGNQRA 84