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 638267780   5 RDRNKKELLELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLSGISKVKSIRLDFWEDDLVERMKTQGNLVA 84
Cdd:cd08844    1 RDRNKKRLLELLKLPGNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLPDISRVKSIRLDFWEDELVEFMKENGNLKA 80

                         90       100       110
                 ....*....|....*....|....*....|..
gi 638267780  85 KNHFEADVPLFYYRPQASDCMVLKDQWIRAKY 116
Cdd:cd08844   81 KAKFEAFVPPFYYRPQANDCDVLKEQWIRAKY 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 638267780 256 NYAMEGYMEKTGPTQREPFKKRWFTLDalDRRLMYLKDPLDAFAQGEVFIGNSECHYSVKEGLQSRSRGnRWSHGFTLVT 335
Cdd:cd01251    1 DFLKEGYLEKTGPKQTDGFRKRWFTLD--DRRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVT 77

                         90       100
                 ....*....|....*....|....*.
gi 638267780 336 PERAFLLTCENEQDFKQWMAAFREII 361
Cdd:cd01251   78 PDRTFLLSAETEEERREWITAIQKVL 103

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 638267780   5 RDRNKKELLELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLSGISKVKSIRLDFWEDDLVERMKTQGNLVA 84
Cdd:cd08844    1 RDRNKKRLLELLKLPGNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLPDISRVKSIRLDFWEDELVEFMKENGNLKA 80

                         90       100       110
                 ....*....|....*....|....*....|..
gi 638267780  85 KNHFEADVPLFYYRPQASDCMVLKDQWIRAKY 116
Cdd:cd08844   81 KAKFEAFVPPFYYRPQANDCDVLKEQWIRAKY 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 638267780 256 NYAMEGYMEKTGPTQREPFKKRWFTLDalDRRLMYLKDPLDAFAQGEVFIGNSECHYSVKEGLQSRSRGnRWSHGFTLVT 335
Cdd:cd01251    1 DFLKEGYLEKTGPKQTDGFRKRWFTLD--DRRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVT 77

                         90       100
                 ....*....|....*....|....*.
gi 638267780 336 PERAFLLTCENEQDFKQWMAAFREII 361
Cdd:cd01251   78 PDRTFLLSAETEEERREWITAIQKVL 103

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 638267780    12 LLELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNL-SGISKVKSIRLDFWEDDLVERMKTQGNLVAKNHFEA 90
Cdd:smart00105   1 LKLLRSIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSLgVHISKVRSLTLDTWTEEELRLLQKGGNENANSIWES 80

                           90       100       110
                   ....*....|....*....|....*....|....*...
gi 638267780    91 DVPLFYYRPQASDCMVLKDQWIRAKYEREEFTGVDSQR 128
Cdd:smart00105  81 NLDDFSLKPPDDDDQQKYESFIAAKYEEKLFVPPESAE 118

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 638267780   259 MEGYMEKTGPTQREPFKKRWFTLDalDRRLMYLKDP---LDAFAQGEVFIGNSECHYSVKEglqsrsRGNRWSHGFTLVT 335
Cdd:smart00233   3 KEGWLYKKSGGGKKSWKKRYFVLF--NSTLLYYKSKkdkKSYKPKGSIDLSGCTVREAPDP------DSSKKPHCFEIKT 74

                           90       100
                   ....*....|....*....|....*..
gi 638267780   336 PERA-FLLTCENEQDFKQWMAAFREII 361
Cdd:smart00233  75 SDRKtLLLQAESEEEREKWVEALRKAI 101

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 638267780  259 MEGYMEKTGPTQREPFKKRWFTLDalDRRLMYLKDPL---DAFAQGEVFIGNSEchysVKEGLQSRSRGNRWSHGFTLV- 334
Cdd:pfam00169   3 KEGWLLKKGGGKKKSWKKRYFVLF--DGSLLYYKDDKsgkSKEPKGSISLSGCE----VVEVVASDSPKRKFCFELRTGe 76

                          90       100
                  ....*....|....*....|....*...
gi 638267780  335 -TPERAFLLTCENEQDFKQWMAAFREII 361
Cdd:pfam00169  77 rTGKRTYLLQAESEEERKDWIKAIQSAI 104

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 638267780   5 RDRNKKELLELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLSGISKVKSIRLDFWEDDLVERMKTQGNLVA 84
Cdd:cd08844    1 RDRNKKRLLELLKLPGNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLPDISRVKSIRLDFWEDELVEFMKENGNLKA 80

                         90       100       110
                 ....*....|....*....|....*....|..
gi 638267780  85 KNHFEADVPLFYYRPQASDCMVLKDQWIRAKY 116
Cdd:cd08844   81 KAKFEAFVPPFYYRPQANDCDVLKEQWIRAKY 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 638267780 135 GKRVGELWKRGRDNGTFLKRNFILSQKEGTLQYYVKE-AKGPKAVIRVADLNATLQPEKVGNPNGMQISYLKDGRTRNMF 213
Cdd:cd13252    1 GSKEGFLWKRGKDNNQFKQRKFVLSEREGTLKYFVKEdAKEPKAVISIEELNATFQPEKIGHPNGLQITYLKDGSTRNIF 80

                         90       100
                 ....*....|....*....|....*....
gi 638267780 214 VYHSKGKEIVDWLNAIRGARLQYLKEAFP 242
Cdd:cd13252   81 VYHEDGKEIVDWYNAIRAARLHYLQVAFP 109

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 638267780 256 NYAMEGYMEKTGPTQREPFKKRWFTLDalDRRLMYLKDPLDAFAQGEVFIGNSECHYSVKEGLQSRSRGnRWSHGFTLVT 335
Cdd:cd01251    1 DFLKEGYLEKTGPKQTDGFRKRWFTLD--DRRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVT 77

                         90       100
                 ....*....|....*....|....*.
gi 638267780 336 PERAFLLTCENEQDFKQWMAAFREII 361
Cdd:cd01251   78 PDRTFLLSAETEEERREWITAIQKVL 103

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 638267780    9 KKELLELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLSG-ISKVKSIRLDFWEDDLVERMKTQGNLVAKNH 87
Cdd:pfam01412   1 KRVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLGVhISKVRSLTLDTWTDEQLELMKAGGNDRANEF 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 638267780   88 FEADVPLFYYRPQaSDCMVLKDQWIRAKYEREEFTGVD 125
Cdd:pfam01412  81 WEANLPPSYKPPP-SSDREKRESFIRAKYVEKKFAKPG 117

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 638267780  12 LLELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLSG-ISKVKSIRLDFWEDDLVERMKTQGNLVAKNHFEA 90
Cdd:cd08839    1 LAKLLREEDNKYCADCGAKGPRWASWNLGVFICIRCAGIHRNLGVhISKVKSVNLDSWTPEQVQSMQEMGNARANAYYEA 80

                         90       100
                 ....*....|....*....|....*.
gi 638267780  91 DVPLFYYRPQASDCMvlkDQWIRAKY 116
Cdd:cd08839   81 NLPDGFRRPQTDSAL---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 638267780  20 GNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNL-SGISKVKSIRLDFWEDDLVERMKTQGNLVAKNHFEADVPLfYYR 98
Cdd:cd08836   11 GNDHCVDCGAPNPDWASLNLGALMCIECSGIHRNLgTHISRVRSLDLDDWPVELLKVMSAIGNDLANSVWEGNTQG-RTK 89

                         90
                 ....*....|....*....
gi 638267780  99 PQASDCMVLKDQWIRAKYE 117
Cdd:cd08836   90 PTPDSSREEKERWIRAKYE 108

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 638267780  14 ELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLsG--ISKVKSIRLDFWEDDLVERMKTQGNLVAKNHFEAD 91
Cdd:cd08835    6 QVLSVPGNAQCCDCGSPDPRWASINLGVTLCIECSGIHRSL-GvhVSKVRSLTLDSWEPELLKVMLELGNDVVNRIYEAN 84

                         90       100       110
                 ....*....|....*....|....*....|.
gi 638267780  92 VPLFYYRPQASDC-MVLKDQWIRAKYEREEF 121
Cdd:cd08835   85 VPDDGSVKPTPDSsRQEREAWIRAKYVEKKF 115

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 638267780  20 GNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNL-SGISKVKSIRLDFWEDDLVERMKTQGNLVAKNHFEADVPlFYYR 98
Cdd:cd08855   13 GNSFCIDCDAPNPDWASLNLGALMCIECSGIHRNLgTHLSRVRSLDLDDWPVELSMVMTAIGNAMANSVWEGALD-GYSK 91

                         90
                 ....*....|....*....
gi 638267780  99 PQASDCMVLKDQWIRAKYE 117
Cdd:cd08855   92 PGPDSTREEKERWIRAKYE 110

ARF1 GTPase-activating protein 1-like; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 638267780   9 KKELLELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLsG--ISKVKSIRLDFWEDDLVERMKTQGNLVAKN 86
Cdd:cd08959    2 RAVFKKLRSKPENKVCFDCGAKNPQWASVTYGIFICLDCSGVHRGL-GvhISFVRSTTMDKWTEEQLRKMKVGGNANARE 80

                 ....
gi 638267780  87 HFEA 90
Cdd:cd08959   81 FFKQ 84

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 638267780  20 GNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLS-GISKVKSIRLDFWEDDLVERMKTQGNLVAKNHFEADV-PLFYY 97
Cdd:cd08851   12 GNASCCDCGLADPRWASINLGITLCIECSGIHRSLGvHFSKVRSLTLDTWEPELLKLMCELGNDVINRIYEARVeKMGAK 91

                         90       100
                 ....*....|....*....|....
gi 638267780  98 RPQASDCMVLKDQWIRAKYEREEF 121
Cdd:cd08851   92 KPQPGGQRQEKEAYIRAKYVERKF 115

ArfGAP with GTPase domain, ANK repeat and PH domain 2; 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 638267780  20 GNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNL-SGISKVKSIRLDFWEDDLVERMKTQGNLVAKNHFEADVPlFYYR 98
Cdd:cd08853   12 GNSHCVDCETQNPKWASLNLGVLMCIECSGIHRNLgTHLSRVRSLDLDDWPVELRKVMSSIGNELANSIWEGSSQ-GQTK 90

                         90
                 ....*....|....*....
gi 638267780  99 PQASDCMVLKDQWIRAKYE 117
Cdd:cd08853   91 PSSDSTREEKERWIRAKYE 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 638267780  20 GNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLS-GISKVKSIRLDFWEDDLVERMKTQGNLVAKNHFEADVPLfYYR 98
Cdd:cd08834   14 GNDVCCDCGSPDPTWLSTNLGILTCIECSGVHRELGvHVSRIQSLTLDNLGTSELLLARNLGNEGFNEIMEANLPP-GYK 92

                         90       100
                 ....*....|....*....|....
gi 638267780  99 PQASDCMVLKDQWIRAKYEREEFT 122
Cdd:cd08834   93 PTPNSDMEERKDFIRAKYVEKKFV 116

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing proteins; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 638267780  20 GNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNL-SGISKVKSIRLD--FWEDDLVERMKTQGNLVAKNHFEADVP 93
Cdd:cd08837   12 ANRFCADCGAPDPDWASINLCVVICKQCAGEHRSLgSNISKVRSLKMDtkVWTEELVELFLKLGNDRANRFWAANLP 88

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 638267780  14 ELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLS-GISKVKSIRLDFWEDDLVERMKTQGNLVAKNHFEADV 92
Cdd:cd08848    8 DVQRLPGNEVCCDCGSPDPTWLSTNLGILTCIECSGIHREMGvHISRIQSLELDKLGTSELLLAKNVGNNSFNDIMEGNL 87

                         90       100       110
                 ....*....|....*....|....*....|
gi 638267780  93 PLFYYRPQASDCMVLKDQWIRAKYEREEFT 122
Cdd:cd08848   88 PSPSPKPSPSSDMTARKEYITAKYVEHRFS 117

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 1; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics. ARAP1 localizes to the plasma membrane, the Golgi complex, and endosomal compartments. It displays PI(3,4,5)P3-dependent ArfGAP activity that regulates Arf-, RhoA-, and Cdc42-dependent cellular events. For example, ARAP1 inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 638267780  20 GNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNL-SGISKVKSIRLD--FWEDDLVERMKTQGNLVAKNHFEADVP 93
Cdd:cd17901   12 SNRFCADCGSPKPDWASVNLCVVICKRCAGEHRGLgPSVSKVRSLKMDrkVWTEELIELFLLLGNGKANQFWAANVP 88

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 3; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics. ARAP3 possesses a unique dual-specificity GAP activity for Arf6 and RhoA regulated by PI(3,4,5)P3 and a small GTPase Rap1-GTP. The RhoGAP activity of ARAP3 is enhanced by direct binding of Rap1-GTP to the Ras-association (RA) domain. ARAP3 is involved in regulation of cell shape and adhesion.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 638267780  21 NSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNL-SGISKVKSIRLD--FWEDDLVERMKTQGNLVAKNHFEADVP 93
Cdd:cd17902   13 NRFCADCHASSPDWASINLCVVICKQCAGQHRSLgSGISKVQSLKLDtsVWSNEIVQLFIVLGNDRANRFWAARLP 88

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 638267780   259 MEGYMEKTGPTQREPFKKRWFTLDalDRRLMYLKDP---LDAFAQGEVFIGNSECHYSVKEglqsrsRGNRWSHGFTLVT 335
Cdd:smart00233   3 KEGWLYKKSGGGKKSWKKRYFVLF--NSTLLYYKSKkdkKSYKPKGSIDLSGCTVREAPDP------DSSKKPHCFEIKT 74

                           90       100
                   ....*....|....*....|....*..
gi 638267780   336 PERA-FLLTCENEQDFKQWMAAFREII 361
Cdd:smart00233  75 SDRKtLLLQAESEEEREKWVEALRKAI 101

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 638267780   8 NKKELLELLKQ----HGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLS-GISKVKSIRLDF-WEDDLVERMKTQGN 81
Cdd:cd09029    2 NKTEIQTLFKRlraiPTNKACFDCGAKNPSWASITYGVFLCIDCSGVHRSLGvHLSFIRSTELDSnWNWFQLRCMQVGGN 81

                 ....*..
gi 638267780  82 LVAKNHF 88
Cdd:cd09029   82 ANATAFF 88

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 638267780  259 MEGYMEKTGPTQREPFKKRWFTLDalDRRLMYLKDPL---DAFAQGEVFIGNSEchysVKEGLQSRSRGNRWSHGFTLV- 334
Cdd:pfam00169   3 KEGWLLKKGGGKKKSWKKRYFVLF--DGSLLYYKDDKsgkSKEPKGSISLSGCE----VVEVVASDSPKRKFCFELRTGe 76

                          90       100
                  ....*....|....*....|....*...
gi 638267780  335 -TPERAFLLTCENEQDFKQWMAAFREII 361
Cdd:pfam00169  77 rTGKRTYLLQAESEEERKDWIKAIQSAI 104

GIT2 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 638267780  24 CADCGIPEPEWASYTLGIFVCLNCSGMHRNLS-GISKVKSIRLDFWEDDLVERMKTQGNLVAKNHFE------ADVPLFY 96
Cdd:cd08847   11 CADCSTSDPRWASVNRGVLICDECCSVHRSLGrHISQVRHLKHTSWPPTLLQMVQTLYNNGANSIWEhslldpASIMSGK 90

                         90       100
                 ....*....|....*....|.
gi 638267780  97 YRPQASDCM-VLKDQWIRAKY 116
Cdd:cd08847   91 RKANPQDKVhPNKAEFIRAKY 111

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 638267780  10 KELLELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLSGISKVKSIRLDFWEDDLVERMKTQGNLVAK 85
Cdd:cd08857    3 KMLREMTSLPHNRKCFDCDQRGPTYANMTVGSFVCTSCSGILRGLNPPHRVKSISMTTFTQQEIEFLQKHGNEVCK 78

hypothetical protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 638267780   4 DRDRNKKELLELLKQHGNSQCADCGIPEPEWASYTLGIFVCLNCSGMHRNLSgiSKVKSIRLDFWEDDLVERMKTQGNLV 83
Cdd:PLN03131   6 EEERNEKIIRGLMKLPPNRRCINCNSLGPQFVCTNFWTFICMTCSGIHREFT--HRVKSVSMSKFTSQDVEALQNGGNQR 83