RhoGAP_ARAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in ARAPs. ARAPs (also known as centaurin deltas) contain, besides the RhoGAP domain, an Arf GAP, ankyrin repeat ras-associating, and PH domains. Since their ArfGAP activity is PIP3-dependent, ARAPs are considered integration points for phosphoinositide, Arf and Rho signaling. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1112 DGNALQDQQLCKNDVPIIVNSCIAFVTQYGLGCKYIYQKDGDPLHISELLESFKKDARSVKLRAGKHQLEDVTGVLKSFL 1191
Cdd:cd04385     1 DGPALEDQQLTDNDIPVIVDKCIDFITQHGLMSEGIYRKNGKNSSVKKLLEAFRKDARSVQLREGEYTVHDVADVLKRFL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1192 SDIDDALLTKELYPYWVSALDTQDEKERTSKYRAFIRSLPGVNRATLAALIEHLYRVQKCSEINHMNAHNLAMVFSSCLF 1271
Cdd:cd04385    81 RDLPDPLLTSELHAEWIEAAELENKDERIARYKELIRRLPPINRATLKVLIGHLYRVQKHSDENQMSVHNLALVFGPTLF 160

                         170       180
                  ....*....|....*....|....
gi 568933964 1272 QTK----GQTSEEVNVIEDLINNY 1291
Cdd:cd04385   161 QTDehsvGQTSHEVKVIEDLIDNY 184

Ras-associating (RA) domain found in Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 2 (ARAP2); ARAP2, also termed Centaurin-delta-1 (Cnt-d1), or Protein PARX, is a phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3))-dependent Arf Rap-activated guanosine triphosphatase (GTPase)-activating protein (GAP), which promotes GLUT1-mediated basal glucose uptake by modifying sphingolipid metabolism through glucosylceramide synthase (GCS). ARAP2 signals through Arf6 and Rac1 to control focal adhesion morphology. ARAP2 contains multiple functional domains, including ArfGAP and RhoGAP domains, as well as a sterile alpha motif (Sam) domain, five PH domains, and a RA domain. The RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub); Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1323 AGDLLIEVFVERKEPDCSIIIRISPVMEAEELTNDILAIKNIIPMKGDIWATFEVIENEELERPLHYTENVLEQVLQWSS 1402
Cdd:cd17227     1 AGDLLIEVYLEKKEPDCSIIIRVSPTMEAEELTNDVLEIKNIIPDKKDIWATFEVIENGELERPLHYKENVLEQVLQWSS 80

                          90
                  ....*....|....*...
gi 568933964 1403 LAEPGSAYLVVKRFLTID 1420
Cdd:cd17227    81 LSEPGSAYLIVKRFQAAD 98

Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1426 REKSIKEGILKLKEEPSKILSGNKFQDRCVVLRDGHLFIYKDPKSSKHDKMFPLRAMKFYLGVKKKMKPPTSWGLTVYSE 1505
Cdd:cd13259    10 KVGSTKHGMLKFREEPSKLLSGNKFQDRYFILNDECLLLYKDVKSSKPEKEWPLKSLKVYLGIKKKLKPPTSWGFTVLLE 89

                          90       100
                  ....*....|....*....|....*
gi 568933964 1506 KHHWHLCCDSLQAQMEWMASIFIAQ 1530
Cdd:cd13259    90 KQQWYLCCDSQMEQREWMATILSAQ 114

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 2; 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 second 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 568933964  583 AVAPEKCGYLELRGYKAKIFTVLRGNSVWLCKNEQDFKSGLGITIIPMNVANVKQVDRavkQSFEIITPYRSFSFTADSE 662
Cdd:cd13254     3 KPNPDKCGYLELRGYKAKVYAALMGDEVWLYKNEQDFRLGIGITVIEMNGANVKDVDR---RSFDLTTPYRSFSFTAESE 79

                          90
                  ....*....|.
gi 568933964  663 REKQEWIEAVQ 673
Cdd:cd13254    80 HEKQEWIEAVQ 90

SAM domain of Arap1,2,3 (angiotensin receptor-associated protein); SAM (sterile alpha motif) domain of Arap1,2,3 subfamily proteins (angiotensin receptor-associated) is a protein-protein interaction domain. Arap1,2,3 proteins are phosphatidylinositol-3,4,5-trisphosphate-dependent GTPase-activating proteins. They are involved in phosphatidylinositol-3 kinase (PI3K) signaling pathways. In addition to SAM domain, Arap1,2,3 proteins contain ArfGap, PH-like, RhoGAP and UBQ domains. SAM domain of Arap3 protein was shown to interact with SAM domain of Ship2 phosphatidylinositol-trisphosphate phosphatase proteins. Such interaction apparently plays a role in inhibition of PI3K regulated pathways since Ship2 converts PI(3,4,5)P3 into PI(3,4)P2. Proteins of this subfamily participate in regulation of signaling and trafficking associated with a number of different receptors (including EGFR, TRAIL-R1/DR4, TRAIL-R2/DR5) in normal and cancer cells; they are involved in regulation of actin cytoskeleton remodeling, cell spreading and formation of lamellipodia.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 568933964    6 EVNADIRDFLMSINLEQYLLHFREFGFYTVRDCTSINDSVLHQIGISPTGHRRRILKQLQMIF 68
Cdd:cd09490     1 EADLDIAEWLASIHLEQYLDLFREHGYVTATDCQGINDSRLKQIGISPTGHRRRILKQLPIIT 63

RhoGAP_ARAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in ARAPs. ARAPs (also known as centaurin deltas) contain, besides the RhoGAP domain, an Arf GAP, ankyrin repeat ras-associating, and PH domains. Since their ArfGAP activity is PIP3-dependent, ARAPs are considered integration points for phosphoinositide, Arf and Rho signaling. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1112 DGNALQDQQLCKNDVPIIVNSCIAFVTQYGLGCKYIYQKDGDPLHISELLESFKKDARSVKLRAGKHQLEDVTGVLKSFL 1191
Cdd:cd04385     1 DGPALEDQQLTDNDIPVIVDKCIDFITQHGLMSEGIYRKNGKNSSVKKLLEAFRKDARSVQLREGEYTVHDVADVLKRFL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1192 SDIDDALLTKELYPYWVSALDTQDEKERTSKYRAFIRSLPGVNRATLAALIEHLYRVQKCSEINHMNAHNLAMVFSSCLF 1271
Cdd:cd04385    81 RDLPDPLLTSELHAEWIEAAELENKDERIARYKELIRRLPPINRATLKVLIGHLYRVQKHSDENQMSVHNLALVFGPTLF 160

                         170       180
                  ....*....|....*....|....
gi 568933964 1272 QTK----GQTSEEVNVIEDLINNY 1291
Cdd:cd04385   161 QTDehsvGQTSHEVKVIEDLIDNY 184

Ras-associating (RA) domain found in Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 2 (ARAP2); ARAP2, also termed Centaurin-delta-1 (Cnt-d1), or Protein PARX, is a phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3))-dependent Arf Rap-activated guanosine triphosphatase (GTPase)-activating protein (GAP), which promotes GLUT1-mediated basal glucose uptake by modifying sphingolipid metabolism through glucosylceramide synthase (GCS). ARAP2 signals through Arf6 and Rac1 to control focal adhesion morphology. ARAP2 contains multiple functional domains, including ArfGAP and RhoGAP domains, as well as a sterile alpha motif (Sam) domain, five PH domains, and a RA domain. The RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub); Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1323 AGDLLIEVFVERKEPDCSIIIRISPVMEAEELTNDILAIKNIIPMKGDIWATFEVIENEELERPLHYTENVLEQVLQWSS 1402
Cdd:cd17227     1 AGDLLIEVYLEKKEPDCSIIIRVSPTMEAEELTNDVLEIKNIIPDKKDIWATFEVIENGELERPLHYKENVLEQVLQWSS 80

                          90
                  ....*....|....*...
gi 568933964 1403 LAEPGSAYLVVKRFLTID 1420
Cdd:cd17227    81 LSEPGSAYLIVKRFQAAD 98

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 5; 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 five 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 568933964 1426 REKSIKEGILKLKEEPSKILSGNKFQDRCVVLRDGHLFIYKDPKSSKHDKMFPLRAMKFYLGVKKKMKPPTSWGLTVYSE 1505
Cdd:cd13259    10 KVGSTKHGMLKFREEPSKLLSGNKFQDRYFILNDECLLLYKDVKSSKPEKEWPLKSLKVYLGIKKKLKPPTSWGFTVLLE 89

                          90       100
                  ....*....|....*....|....*
gi 568933964 1506 KHHWHLCCDSLQAQMEWMASIFIAQ 1530
Cdd:cd13259    90 KQQWYLCCDSQMEQREWMATILSAQ 114

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 2; 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 second 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 568933964  583 AVAPEKCGYLELRGYKAKIFTVLRGNSVWLCKNEQDFKSGLGITIIPMNVANVKQVDRavkQSFEIITPYRSFSFTADSE 662
Cdd:cd13254     3 KPNPDKCGYLELRGYKAKVYAALMGDEVWLYKNEQDFRLGIGITVIEMNGANVKDVDR---RSFDLTTPYRSFSFTAESE 79

                          90
                  ....*....|.
gi 568933964  663 REKQEWIEAVQ 673
Cdd:cd13254    80 HEKQEWIEAVQ 90

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 4; 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 fourth 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 568933964 1013 YDLIGQLFYKDCHALDQWRKGWFAMDKSSLCFCLQTQEAqEERMNLRRLQELTISTMVQNgekvDVLLLVEKGRTLYIHG 1092
Cdd:cd13257     1 FERLGRLFYKDGLALDRAREGWFALDKSSLHACLQMQEV-EERMHLRKLQELSIQGDVQL----DVLVLVERRRTLYIQG 75

                          90
                  ....*....|....*.
gi 568933964 1093 HTKLDFTVWHTAIEKA 1108
Cdd:cd13257    76 ERKLDFTGWHTAIQKA 91

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 568933964   684 EVAEKIWFNESNRSCADCKAPDPDWASINLCVVICKKCAGQHRSLGPKDSKVRSLKMDasIWSNELIELFIVIGNKRAND 763
Cdd:pfam01412    2 RVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLGVHISKVRSLTLD--TWTDEQLELMKAGGNDRANE 79

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 568933964   764 FWAGNLQKDEELQVDSPVEKRKNFITQKYKEGKFRK 799
Cdd:pfam01412   80 FWEANLPPSYKPPPSSDREKRESFIRAKYVEKKFAK 115

SAM domain of Arap1,2,3 (angiotensin receptor-associated protein); SAM (sterile alpha motif) domain of Arap1,2,3 subfamily proteins (angiotensin receptor-associated) is a protein-protein interaction domain. Arap1,2,3 proteins are phosphatidylinositol-3,4,5-trisphosphate-dependent GTPase-activating proteins. They are involved in phosphatidylinositol-3 kinase (PI3K) signaling pathways. In addition to SAM domain, Arap1,2,3 proteins contain ArfGap, PH-like, RhoGAP and UBQ domains. SAM domain of Arap3 protein was shown to interact with SAM domain of Ship2 phosphatidylinositol-trisphosphate phosphatase proteins. Such interaction apparently plays a role in inhibition of PI3K regulated pathways since Ship2 converts PI(3,4,5)P3 into PI(3,4)P2. Proteins of this subfamily participate in regulation of signaling and trafficking associated with a number of different receptors (including EGFR, TRAIL-R1/DR4, TRAIL-R2/DR5) in normal and cancer cells; they are involved in regulation of actin cytoskeleton remodeling, cell spreading and formation of lamellipodia.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 568933964    6 EVNADIRDFLMSINLEQYLLHFREFGFYTVRDCTSINDSVLHQIGISPTGHRRRILKQLQMIF 68
Cdd:cd09490     1 EADLDIAEWLASIHLEQYLDLFREHGYVTATDCQGINDSRLKQIGISPTGHRRRILKQLPIIT 63

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 568933964    483 KCGWLDKLSPQGKRMFQKRWVKFDGLSISYYNNDREMYS---KGIIPLTAIS------TVRAQGDNKFEIVTTQR-TFVF 552
Cdd:smart00233    3 KEGWLYKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSykpKGSIDLSGCTvreapdPDSSKKPHCFEIKTSDRkTLLL 82

                            90       100
                    ....*....|....*....|
gi 568933964    553 RVEKEEERNDWISILLSALK 572
Cdd:smart00233   83 QAESEEEREKWVEALRKAIA 102

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964  677 AETLSD-YEVAEKIWFNESNRSCADCKAPDPDWASINLCVVICKKCAGQHRSLGPKDSKVRSLKMDAsiWSNELIELFIV 755
Cdd:PLN03114    3 SENLNDkISVFKKLKAKSDNKICFDCNAKNPTWASVTYGIFLCIDCSAVHRSLGVHISFVRSTNLDS--WSSEQLKMMIY 80

                          90
                  ....*....|
gi 568933964  756 IGNKRANDFW 765
Cdd:PLN03114   81 GGNNRAQVFF 90

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 568933964    586 PEKCGYLELRGYKA-----KIFTVLRGNSVWLCKNEQDFKSGLGITIIPMNVANVKQVDRA----VKQSFEIITPYR-SF 655
Cdd:smart00233    1 VIKEGWLYKKSGGGkkswkKRYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCTVREAPDPdsskKPHCFEIKTSDRkTL 80

                            90       100
                    ....*....|....*....|..
gi 568933964    656 SFTADSEREKQEWIEAVQQSIA 677
Cdd:smart00233   81 LLQAESEEEREKWVEALRKAIA 102

SAM domain (Sterile alpha motif); It has been suggested that SAM is an evolutionarily conserved protein binding domain that is involved in the regulation of numerous developmental processes in diverse eukaryotes. The SAM domain can potentially function as a protein interaction module through its ability to homo- and heterooligomerise with other SAM domains.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 568933964    10 DIRDFLMSINLEQYLLHFREfGFYTVRDCTSINDSVLHQIGISPTGHRRRILKQLQMI 67
Cdd:pfam00536    7 DVGEWLESIGLGQYIDSFRA-GYIDGDALLQLTEDDLLKLGVTLLGHRKKILYAIQRL 63

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Recent evidence (not yet in MEDLINE) shows that some RA domains do NOT bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964  1328 IEVFVERKEPDC-SIIIRISPVMEAEELTNDILAIKNIIPMKGDiWATFEVIENEELERPLHYTENVLEQVLQWSSlaEP 1406
Cdd:pfam00788    5 LKVYTEDGKPGTtYKTILVSSSTTAEEVIEALLEKFGLEDDPRD-YVLVEVLERGGGERRLPDDECPLQIQLQWPR--DA 81

                   ....*....
gi 568933964  1407 GSAYLVVKR 1415
Cdd:pfam00788   82 SDSRFLLRK 90

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964  1430 IKEGILKLKEEPSKilsgNKFQDRCVVLRDGHLFIYKDPKSSKHDK---MFPLRAMKFYLGVKKKMKP-PTSWGLTVY-- 1503
Cdd:pfam00169    2 VKEGWLLKKGGGKK----KSWKKRYFVLFDGSLLYYKDDKSGKSKEpkgSISLSGCEVVEVVASDSPKrKFCFELRTGer 77

                           90       100
                   ....*....|....*....|...
gi 568933964  1504 SEKHHWHLCCDSLQAQMEWMASI 1526
Cdd:pfam00169   78 TGKRTYLLQAESEEERKDWIKAI 100

RhoGAP_ARAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in ARAPs. ARAPs (also known as centaurin deltas) contain, besides the RhoGAP domain, an Arf GAP, ankyrin repeat ras-associating, and PH domains. Since their ArfGAP activity is PIP3-dependent, ARAPs are considered integration points for phosphoinositide, Arf and Rho signaling. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1112 DGNALQDQQLCKNDVPIIVNSCIAFVTQYGLGCKYIYQKDGDPLHISELLESFKKDARSVKLRAGKHQLEDVTGVLKSFL 1191
Cdd:cd04385     1 DGPALEDQQLTDNDIPVIVDKCIDFITQHGLMSEGIYRKNGKNSSVKKLLEAFRKDARSVQLREGEYTVHDVADVLKRFL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1192 SDIDDALLTKELYPYWVSALDTQDEKERTSKYRAFIRSLPGVNRATLAALIEHLYRVQKCSEINHMNAHNLAMVFSSCLF 1271
Cdd:cd04385    81 RDLPDPLLTSELHAEWIEAAELENKDERIARYKELIRRLPPINRATLKVLIGHLYRVQKHSDENQMSVHNLALVFGPTLF 160

                         170       180
                  ....*....|....*....|....
gi 568933964 1272 QTK----GQTSEEVNVIEDLINNY 1291
Cdd:cd04385   161 QTDehsvGQTSHEVKVIEDLIDNY 184

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964  683 YEVAEKIWFNESNRSCADCKAPDPDWASINLCVVICKKCAGQHRSLGPKDSKVRSLKMDASIWSNELIELFIVIGNKRAN 762
Cdd:cd08837     1 YEVAEKIWSNPANRFCADCGAPDPDWASINLCVVICKQCAGEHRSLGSNISKVRSLKMDTKVWTEELVELFLKLGNDRAN 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 568933964  763 DFWAGNLQKDEELQVDSPVEKRKNFITQKYKEGKFR 798
Cdd:cd08837    81 RFWAANLPPSEALHPDADSEQRREFITAKYREGKYR 116

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964  683 YEVAEKIWFNESNRSCADCKAPDPDWASINLCVVICKKCAGQHRSLGPKDSKVRSLKMDASIWSNELIELFIVIGNKRAN 762
Cdd:cd17902     1 YEVAEKIWSNKANRFCADCHASSPDWASINLCVVICKQCAGQHRSLGSGISKVQSLKLDTSVWSNEIVQLFIVLGNDRAN 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 568933964  763 DFWAGNLQKDEELQVDSPVEKRKNFITQKYKEGKFR 798
Cdd:cd17902    81 RFWAARLPASEALHPDATPEQRREFISRKYREGRFR 116

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 3; 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 third 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 568933964  890 SSFLCDFLYQTAAAASRVSsEKKLLEDTNKKWCVLEGGFLSYYENDRCTTPNGTINISEVICLAVHKEDFYLNTGPIFVF 969
Cdd:cd13256     1 SVFHSGFLYKSPSAAKPTL-ERRAREEFSRRWCVLEDGFLSYYESERSPEPNGEIDVSEIVCLAVSPPDTHPGDGFPFTF 79

                          90       100       110
                  ....*....|....*....|....*....|.
gi 568933964  970 EIYLPSERVFLFGAETSQIQRKWTETIAKRF 1000
Cdd:cd13256    80 ELYLESERLYLFGLETAEALHEWVKAIAKAF 110

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 568933964  482 EKCGWLDKLSPQG-KRMFQKRWVKFDGLSISYYNNDREMYSKGIIPLTAISTVRAQGDNKFEIVTTQRTFVFRVEKEEER 560
Cdd:cd13253     1 IKSGYLDKQGGQGnNKGFQKRWVVFDGLSLRYFDSEKDAYSKRIIPLSAISTVRAVGDNKFELVTTNRTFVFRAESDDER 80

                          90
                  ....*....|...
gi 568933964  561 NDWISILLSALKS 573
Cdd:cd13253    81 NLWCSTLQAAISE 93

RhoGAP domain; GTPase activator proteins towards Rho/Rac/Cdc42-like small GTPases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964  1127 PIIVNSCIAFVTQYGLGCKYIYQKDGDPLHISELLESFKKDARSVkLRAGKHQLEDVTGVLKSFLSDIDDALLTKELYPY 1206
Cdd:pfam00620    1 PLIVRKCVEYLEKRGLDTEGIFRVSGSASRIKELREAFDRGPDVD-LDLEEEDVHVVASLLKLFLRELPEPLLTFELYEE 79

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 568933964  1207 WVSALDTQDEKERTSKYRAFIRSLPGVNRATLAALIEHLYRVQKCSEINHMNAHNLAMVFSSCLFQTK 1274
Cdd:pfam00620   80 FIEAAKLPDEEERLEALRELLRKLPPANRDTLRYLLAHLNRVAQNSDVNKMNAHNLAIVFGPTLLRPP 147

GTPase-activator protein for Rho-like GTPases; GTPase activator proteins towards Rho/Rac/Cdc42-like small GTPases. etter domain limits and outliers.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964   1125 DVPIIVNSCIAFVTQYGLGCKYIYQKDGDPLHISELLESFKKDARSVkLRAGKHQLEDVTGVLKSFLSDIDDALLTKELY 1204
Cdd:smart00324    2 PIPIIVEKCIEYLEKRGLDTEGIYRVSGSKSRVKELRDAFDSGPDPD-LDLSEYDVHDVAGLLKLFLRELPEPLITYELY 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964   1205 PYWVSALDTQDEKERTSKYRAFIRSLPGVNRATLAALIEHLYRVQKCSEINHMNAHNLAMVFSSCLFQTKGQTSEEV--- 1281
Cdd:smart00324   81 EEFIEAAKLEDETERLRALRELLSLLPPANRATLRYLLAHLNRVAEHSEENKMTARNLAIVFGPTLLRPPDGEVASLkdi 160

                           170
                    ....*....|....
gi 568933964   1282 ----NVIEDLINNY 1291
Cdd:smart00324  161 rhqnTVIEFLIENA 174

GTPase-activating protein (GAP) for the ADP ribosylation factors (ARFs); ArfGAPs are a family of proteins containing an ArfGAP catalytic domain that induces the hydrolysis of GTP bound to the small guanine nucleotide-binding protein Arf, a member of the Ras superfamily of GTPases. Like all GTP-binding proteins, Arf proteins function as molecular switches, cycling between GTP (active-membrane bound) and GDP (inactive-cytosolic) form. Conversion to the GTP-bound form requires a guanine nucleotide exchange factor (GEF), whereas conversion to the GDP-bound form is catalyzed by a GTPase activating protein (GAP). In that sense, ArfGAPs were originally proposed to function as terminators of Arf signaling, which is mediated by regulating Arf family GTP-binding proteins. However, recent studies suggest that ArfGAPs can also function as Arf effectors, independently of their GAP enzymatic activity to transduce signals in cells. The ArfGAP domain contains a C4-type zinc finger motif and a conserved arginine that is required for activity, within a specific spacing (CX2CX16CX2CX4R). ArfGAPs, which have multiple functional domains, regulate the membrane trafficking and actin cytoskeleton remodeling via specific interactions with signaling lipids such as phosphoinositides and trafficking proteins, which consequently affect cellular events such as cell growth, migration, and cancer invasion. The ArfGAP family, which includes 31 human ArfGAP-domain containing proteins, is divided into 10 subfamilies based on domain structure and sequence similarity. The ArfGAP nomenclature is mainly based on the protein domain structure. For example, ASAP1 contains ArfGAP, SH3, ANK repeat and PH domains; ARAPs contain ArfGAP, Rho GAP, ANK repeat and PH domains; ACAPs contain ArfGAP, BAR (coiled coil), ANK repeat and PH domains; and AGAPs contain Arf GAP, GTP-binding protein-like, ANK repeat and PH domains. Furthermore, the ArfGAPs can be classified into two major types of subfamilies, according to the overall domain structure: the ArfGAP1 type includes 6 subfamilies (ArfGAP1, ArfGAP2/3, ADAP, SMAP, AGFG, and GIT), which contain the ArfGAP domain at the N-terminus of the protein; and the AZAP type includes 4 subfamilies (ASAP, ACAP, AGAP, and ARAP), which contain an ArfGAP domain between the PH and ANK repeat domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964  687 EKIWFNESNRSCADCKAPDPDWASINLCVVICKKCAGQHRSLGPKDSKVRSLKMDAsiWSNELIELFIVIGNKRANDFWA 766
Cdd:cd08204     2 EELLKLPGNKVCADCGAPDPRWASINLGVFICIRCSGIHRSLGVHISKVRSLTLDS--WTPEQVELMKAIGNARANAYYE 79

                          90       100
                  ....*....|....*....|....*..
gi 568933964  767 GNLQKDEELQ-VDSPVEKRKNFITQKY 792
Cdd:cd08204    80 ANLPPGFKKPtPDSSDEEREQFIRAKY 106

RhoGAP: GTPase-activator protein (GAP) for Rho-like GTPases; GAPs towards Rho/Rac/Cdc42-like small GTPases. Small GTPases (G proteins) cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when bound to GDP. The Rho family of small G proteins, which includes Cdc42Hs, activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. G proteins generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude. The RhoGAPs are one of the major classes of regulators of Rho G proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1127 PIIVNSCIAFVTQYGLGCKYIYQKDGDPLHISELLESFKKDARSVKLRagKHQLEDVTGVLKSFLSDIDDALLTKELYPY 1206
Cdd:cd00159     1 PLIIEKCIEYLEKNGLNTEGIFRVSGSASKIEELKKKFDRGEDIDDLE--DYDVHDVASLLKLYLRELPEPLIPFELYDE 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933964 1207 WVSALDTQDEKERTSKYRAFIRSLPGVNRATLAALIEHLYRVQKCSEINHMNAHNLAMVFSSCLF-------QTKGQTSE 1279
Cdd:cd00159    79 FIELAKIEDEEERIEALKELLKSLPPENRDLLKYLLKLLHKISQNSEVNKMTASNLAIVFAPTLLrppdsddELLEDIKK 158

                         170
                  ....*....|.
gi 568933964 1280 EVNVIEDLINN 1290
Cdd:cd00159   159 LNEIVEFLIEN 169

SAM domain of Arap1,2,3 (angiotensin receptor-associated protein); SAM (sterile alpha motif) domain of Arap1,2,3 subfamily proteins (angiotensin receptor-associated) is a protein-protein interaction domain. Arap1,2,3 proteins are phosphatidylinositol-3,4,5-trisphosphate-dependent GTPase-activating proteins. They are involved in phosphatidylinositol-3 kinase (PI3K) signaling pathways. In addition to SAM domain, Arap1,2,3 proteins contain ArfGap, PH-like, RhoGAP and UBQ domains. SAM domain of Arap3 protein was shown to interact with SAM domain of Ship2 phosphatidylinositol-trisphosphate phosphatase proteins. Such interaction apparently plays a role in inhibition of PI3K regulated pathways since Ship2 converts PI(3,4,5)P3 into PI(3,4)P2. Proteins of this subfamily participate in regulation of signaling and trafficking associated with a number of different receptors (including EGFR, TRAIL-R1/DR4, TRAIL-R2/DR5) in normal and cancer cells; they are involved in regulation of actin cytoskeleton remodeling, cell spreading and formation of lamellipodia.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 568933964    6 EVNADIRDFLMSINLEQYLLHFREFGFYTVRDCTSINDSVLHQIGISPTGHRRRILKQLQMIF 68
Cdd:cd09490     1 EADLDIAEWLASIHLEQYLDLFREHGYVTATDCQGINDSRLKQIGISPTGHRRRILKQLPIIT 63

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 568933964  695 NRSCADCKAPDPDWASINLCVVICKKCAGQHRSLGPKDSKVRSLKMDAsiWSNELIELFIVIGNKRANDFWAGNLQKDEE 774
Cdd:cd08836    12 NDHCVDCGAPNPDWASLNLGALMCIECSGIHRNLGTHISRVRSLDLDD--WPVELLKVMSAIGNDLANSVWEGNTQGRTK 89

                          90
                  ....*....|....*...
gi 568933964  775 LQVDSPVEKRKNFITQKY 792
Cdd:cd08836    90 PTPDSSREEKERWIRAKY 107