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 1622026232 1015 GDTLSEQQLTDTDVPIIVDRCIDYITQCGLTSEGIYRKSGQNSKTTGLLEILRKDARRVRLKEGEHQVDDVANTLKRFFR 1094
Cdd:cd04385      2 GPALEDQQLTDNDIPVIVDKCIDFITQHGLMSEGIYRKNGKNSSVKKLLEAFRKDARSVQLREGEYTVHDVADVLKRFLR 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232 1095 DVEDGLFTKDSSPAWLKATGkaIEDDKEKVGRYRKLLSSLPAVNRATVKALINHLYRVQCFSDMNQMTTHNLAIVFGPTL 1174
Cdd:cd04385     82 DLPDPLLTSELHAEWIEAAE--LENKDERIARYKELIRRLPPINRATLKVLIGHLYRVQKHSDENQMSVHNLALVFGPTL 159

                          170       180
                   ....*....|....*....|....*
gi 1622026232 1175 FQTD----GKDYKAGRVVEDLIRCY 1195
Cdd:cd04385    160 FQTDehsvGQTSHEVKVIEDLIDNY 184

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 1622026232 1323 ENMLLYLASKVGDSKHGMMKFREEKNVLGVGlsTGFHDRYFILNSSCLRLYKEVRSHKPEKEWPVKNLKIYLGIKKKVRP 1402
Cdd:cd13259      1 EAILLYLASKVGSTKHGMLKFREEPSKLLSG--NKFQDRYFILNDECLLLYKDVKSSKPEKEWPLKSLKVYLGIKKKLKP 78

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*...
gi 1622026232 1403 PSCWGFTVFFeneklEKQQWYLCCDTQMELRGWFATFLSVQHGGNIWP 1450
Cdd:cd13259     79 PTSWGFTVLL-----EKQQWYLCCDSQMEQREWMATILSAQHDGDIWP 121

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 1622026232  803 SVAHNGFLYKAPSMAKLVHERKSREEFSRRWCRLHEGIFSYYDNNTSTVPNGEIRMQEVACLVNNPPEAH---GFACTFE 879
Cdd:cd13256      1 SVFHSGFLYKSPSAAKPTLERRAREEFSRRWCVLEDGFLSYYESERSPEPNGEIDVSEIVCLAVSPPDTHpgdGFPFTFE 80

                           90       100       110
                   ....*....|....*....|....*....|
gi 1622026232  880 VYIEAERLYLFGLDCPEAIREWVKCIGKSF 909
Cdd:cd13256     81 LYLESERLYLFGLETAEALHEWVKAIAKAF 110

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 1622026232  922 FERLGRLQYKGGLNLERAKEGWFALAQGTLYAYLEGSEKEEAVHLRKLQELSIQGD--NEVLVLVERRRTLYIQGERKLD 999
Cdd:cd13257      1 FERLGRLFYKDGLALDRAREGWFALDKSSLHACLQMQEVEERMHLRKLQELSIQGDvqLDVLVLVERRRTLYIQGERKLD 80

                           90
                   ....*....|.
gi 1622026232 1000 FLGWVNAIQKA 1010
Cdd:cd13257     81 FTGWHTAIQKA 91

SAM (Sterile alpha motif ); SAM (Sterile Alpha Motif) domain is a module consisting of approximately 70 amino acids. This domain is found in the Fungi/Metazoa group and in a restricted number of bacteria. Proteins with SAM domains are represented by a wide variety of domain architectures and have different intracellular localization, including nucleus, cytoplasm and membranes. SAM domains have diverse functions. They can interact with proteins, RNAs and membrane lipids, contain site of phosphorylation and/or kinase docking site, and play a role in protein homo and hetero dimerization/oligomerization in processes ranging from signal transduction to regulation of transcription. Mutations in SAM domains have been linked to several diseases.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1622026232    4 GASLPMGDWLRALHLEQYAENFERNELWRVSDCQHLSDEALTRLGILLPGHRRRILSGLLKAF 66
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 1622026232 1015 GDTLSEQQLTDTDVPIIVDRCIDYITQCGLTSEGIYRKSGQNSKTTGLLEILRKDARRVRLKEGEHQVDDVANTLKRFFR 1094
Cdd:cd04385      2 GPALEDQQLTDNDIPVIVDKCIDFITQHGLMSEGIYRKNGKNSSVKKLLEAFRKDARSVQLREGEYTVHDVADVLKRFLR 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232 1095 DVEDGLFTKDSSPAWLKATGkaIEDDKEKVGRYRKLLSSLPAVNRATVKALINHLYRVQCFSDMNQMTTHNLAIVFGPTL 1174
Cdd:cd04385     82 DLPDPLLTSELHAEWIEAAE--LENKDERIARYKELIRRLPPINRATLKVLIGHLYRVQKHSDENQMSVHNLALVFGPTL 159

                          170       180
                   ....*....|....*....|....*
gi 1622026232 1175 FQTD----GKDYKAGRVVEDLIRCY 1195
Cdd:cd04385    160 FQTDehsvGQTSHEVKVIEDLIDNY 184

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 1622026232 1323 ENMLLYLASKVGDSKHGMMKFREEKNVLGVGlsTGFHDRYFILNSSCLRLYKEVRSHKPEKEWPVKNLKIYLGIKKKVRP 1402
Cdd:cd13259      1 EAILLYLASKVGSTKHGMLKFREEPSKLLSG--NKFQDRYFILNDECLLLYKDVKSSKPEKEWPLKSLKVYLGIKKKLKP 78

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*...
gi 1622026232 1403 PSCWGFTVFFeneklEKQQWYLCCDTQMELRGWFATFLSVQHGGNIWP 1450
Cdd:cd13259     79 PTSWGFTVLL-----EKQQWYLCCDSQMEQREWMATILSAQHDGDIWP 121

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 1622026232  803 SVAHNGFLYKAPSMAKLVHERKSREEFSRRWCRLHEGIFSYYDNNTSTVPNGEIRMQEVACLVNNPPEAH---GFACTFE 879
Cdd:cd13256      1 SVFHSGFLYKSPSAAKPTLERRAREEFSRRWCVLEDGFLSYYESERSPEPNGEIDVSEIVCLAVSPPDTHpgdGFPFTFE 80

                           90       100       110
                   ....*....|....*....|....*....|
gi 1622026232  880 VYIEAERLYLFGLDCPEAIREWVKCIGKSF 909
Cdd:cd13256     81 LYLESERLYLFGLETAEALHEWVKAIAKAF 110

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232 1029 PIIVDRCIDYITQCGLTSEGIYRKSGQNSKTTGLLEILRKDARRVrLKEGEHQVDDVANTLKRFFRDVEDGLFTKDSSPA 1108
Cdd:pfam00620    1 PLIVRKCVEYLEKRGLDTEGIFRVSGSASRIKELREAFDRGPDVD-LDLEEEDVHVVASLLKLFLRELPEPLLTFELYEE 79

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232 1109 WLKATgkAIEDDKEKVGRYRKLLSSLPAVNRATVKALINHLYRVQCFSDMNQMTTHNLAIVFGPTLFQTD 1178
Cdd:pfam00620   80 FIEAA--KLPDEEERLEALRELLRKLPPANRDTLRYLLAHLNRVAQNSDVNKMNAHNLAIVFGPTLLRPP 147

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 1622026232  922 FERLGRLQYKGGLNLERAKEGWFALAQGTLYAYLEGSEKEEAVHLRKLQELSIQGD--NEVLVLVERRRTLYIQGERKLD 999
Cdd:cd13257      1 FERLGRLFYKDGLALDRAREGWFALDKSSLHACLQMQEVEERMHLRKLQELSIQGDvqLDVLVLVERRRTLYIQGERKLD 80

                           90
                   ....*....|.
gi 1622026232 1000 FLGWVNAIQKA 1010
Cdd:cd13257     81 FTGWHTAIQKA 91

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 1622026232  370 IKAGWLDKNPPQGttllthrapqltvfsgsRSYIYQKRWVKLDSDNLRYFDNEKDVYSKRLIPICCITRVASIGDQKFEV 449
Cdd:cd13253      1 IKSGYLDKQGGQG-----------------NNKGFQKRWVVFDGLSLRYFDSEKDAYSKRIIPLSAISTVRAVGDNKFEL 63

                           90       100       110
                   ....*....|....*....|....*....|.
gi 1622026232  450 ITNNRTFAFRAESDADRNEWIRALQKVVDEK 480
Cdd:cd13253     64 VTTNRTFVFRAESDDERNLWCSTLQAAISEY 94

GTPase-activating protein that regulates ARFs (ADP-ribosylation factors), involved in ARF-mediated vesicular transport [Intracellular trafficking and secretion];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232  596 EVAERIWKVEENCFCADCGSPKPDWGSINLCVVICKRCAGEHRGLGPNVTKVRSLKMDKkvWTEELIELFLQIGNAVANQ 675
Cdd:COG5347      9 KLLKLLKSDSSNKKCADCGAPNPTWASVNLGVFLCIDCAGVHRSLGVHISKVKSLTLDN--WTEEELRRMEVGGNSNANR 86

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 1622026232  676 FWAANVPPSEAVHPR--SDSQERRRFLVAKYREGKYR 710
Cdd:COG5347     87 FYEKNLLDQLLLPIKakYDSSVAKKYIRKKYELKKFI 123

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 1622026232   392 QLTVFSGSRSYIYQKRWVKLDSDNLRYFDNEKDVYS---KRLIPI--CCITRVASIGDQK----FEVITNNR-TFAFRAE 461
Cdd:smart00233    6 WLYKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSykpKGSIDLsgCTVREAPDPDSSKkphcFEIKTSDRkTLLLQAE 85

                            90
                    ....*....|....*..
gi 1622026232   462 SDADRNEWIRALQKVVD 478
Cdd:smart00233   86 SEEEREKWVEALRKAIA 102

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 1622026232 1232 GDFICTVYLEEKKTE-AEQHIKIPATMTAEELTFEILDRRKIvMKEKEFWSCFEVNEREEAERPLHYSEKVLPILHSLGK 1310
Cdd:pfam00788    1 DDGVLKVYTEDGKPGtTYKTILVSSSTTAEEVIEALLEKFGL-EDDPRDYVLVEVLERGGGERRLPDDECPLQIQLQWPR 79

                           90
                   ....*....|.
gi 1622026232 1311 D---SYLVVKK 1318
Cdd:pfam00788   80 DasdSRFLLRK 90

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232  393 LTVFSGSRSYIYQKRWVKLDSDNLRYFDNEKDVYSKRL---IPI--CCITRVASIGDQK----FEVIT----NNRTFAFR 459
Cdd:pfam00169    7 LLKKGGGKKKSWKKRYFVLFDGSLLYYKDDKSGKSKEPkgsISLsgCEVVEVVASDSPKrkfcFELRTgertGKRTYLLQ 86

                           90
                   ....*....|....*...
gi 1622026232  460 AESDADRNEWIRALQKVV 477
Cdd:pfam00169   87 AESEEERKDWIKAIQSAI 104

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232   69 ALPVMDAPKLPPRRPVPmkrnifrPGAATAVSSTEQEAGSDS----AAEASPPRRELEAAPTPPPIPPRTSCHPPLKFSS 144
Cdd:PHA03247  2734 ALPAAPAPPAVPAGPAT-------PGGPARPARPPTTAGPPApappAAPAAGPPRRLTRPAVASLSESRESLPSPWDPAD 2806

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232  145 TAASELPAGPSLLEFTPPARGrlSPDAAAAEETGNPPLPPLPAKRHHLEG----------KPPTQKAPPVPSRPPTLPPr 214
Cdd:PHA03247  2807 PPAAVLAPAAALPPAASPAGP--LPPPTSAQPTAPPPPPGPPPPSLPLGGsvapggdvrrRPPSRSPAAKPAAPARPPV- 2883

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*
gi 1622026232  215 gppqKAAASPPVKNHLQDPEQPPAIFPRLKTVERTSAPEPPSKPP 259
Cdd:PHA03247  2884 ----RRLARPAVSRSTESFALPPDQPERPPQPQAPPPPQPQPQPP 2924

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232 1337 KHGMMKFREEKNvlgvglSTGFHDRYFILNSSCLRLYKE---VRSHKPEKEWPVKNLKIYLgIKKKVRPPSCWGFTVFFe 1413
Cdd:pfam00169    3 KEGWLLKKGGGK------KKSWKKRYFVLFDGSLLYYKDdksGKSKEPKGSISLSGCEVVE-VVASDSPKRKFCFELRT- 74

                           90       100       110
                   ....*....|....*....|....*....|.
gi 1622026232 1414 NEKLEKQQWYLCCDTQMELRGWFATFLSVQH 1444
Cdd:pfam00169   75 GERTGKRTYLLQAESEEERKDWIKAIQSAIR 105

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232   71 PVMDAPKLPPRRPVPMKRNIFRPGAATAVSSTEQEAGSDSAAEASPPRRELEAAPTPPPIPPRTSCHPP-LKFSSTAASE 149
Cdd:pfam03154  172 PVLQAQSGAASPPSPPPPGTTQAATAGPTPSAPSVPPQGSPATSQPPNQTQSTAAPHTLIQQTPTLHPQrLPSPHPPLQP 251

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232  150 LPAGPslleftPPARGRLSPDAAAAEETGNPPLP-PLPAKRHHLEGKPPTQ-----------KAPPVPSrpptLPPRGPP 217
Cdd:pfam03154  252 MTQPP------PPSQVSPQPLPQPSLHGQMPPMPhSLQTGPSHMQHPVPPQpfpltpqssqsQVPPGPS----PAAPGQS 321

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|..
gi 1622026232  218 QKAAASPPVKNHLQdPEQPpaifPRLKTVERTSAPEPPSKPP 259
Cdd:pfam03154  322 QQRIHTPPSQSQLQ-SQQP----PREQPLPPAPLSMPHIKPP 358

PAB1-binding protein, interacts with poly(A)-binding protein [RNA processing and modification];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232   41 DEALTRLGILL-------PGHRRRILSGLLKAFTEALPV----MDAPKLPPRRPVPMKRNIFRP-----GAATAVSSTEQ 104
Cdd:COG5180      1 VRKATILEIRLlatvpipPNAARPVLSPELWAAANNDAVsqgdRSALASSPTRPYARKIFEPLDiklalGKPQLPSVAEP 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232  105 EAGSDSAAE-ASPPRRELEAAPTPPPIPPRtschPPLKFSSTAASELPAGPSLLEFTPP--ARGRLSPDA--AAAEETGN 179
Cdd:COG5180     81 EAYLDPAPPkSSPDTPEEQLGAPAGDLLVL----PAAKTPELAAGALPAPAAAAALPKAkvTREATSASAgvALAAALLQ 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232  180 PPLPPLPAKR-HHLEGKPPTQKAPPVPSRPPTLPPRGPPQKAAASPPVKNHLQDPEQPPAIFPRLKTVERTSAPEPPSKP 258
Cdd:COG5180    157 RSDPILAKDPdGDSASTLPPPAEKLDKVLTEPRDALKDSPEKLDRPKVEVKDEAQEEPPDLTGGADHPRPEAASSPKVDP 236

                          250       260
                   ....*....|....*....|..
gi 1622026232  259 PLLFQTD----VVDSDYEDPPF 276
Cdd:COG5180    237 PSTSEARsrpaTVDAQPEMRPP 258

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 1622026232 1015 GDTLSEQQLTDTDVPIIVDRCIDYITQCGLTSEGIYRKSGQNSKTTGLLEILRKDARRVRLKEGEHQVDDVANTLKRFFR 1094
Cdd:cd04385      2 GPALEDQQLTDNDIPVIVDKCIDFITQHGLMSEGIYRKNGKNSSVKKLLEAFRKDARSVQLREGEYTVHDVADVLKRFLR 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232 1095 DVEDGLFTKDSSPAWLKATGkaIEDDKEKVGRYRKLLSSLPAVNRATVKALINHLYRVQCFSDMNQMTTHNLAIVFGPTL 1174
Cdd:cd04385     82 DLPDPLLTSELHAEWIEAAE--LENKDERIARYKELIRRLPPINRATLKVLIGHLYRVQKHSDENQMSVHNLALVFGPTL 159

                          170       180
                   ....*....|....*....|....*
gi 1622026232 1175 FQTD----GKDYKAGRVVEDLIRCY 1195
Cdd:cd04385    160 FQTDehsvGQTSHEVKVIEDLIDNY 184

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232  596 EVAERIWKVEENCFCADCGSPKPDWGSINLCVVICKRCAGEHRGLGPNVTKVRSLKMDKKVWTEELIELFLQIGNAVANQ 675
Cdd:cd17901      2 EVAEKIWSVESNRFCADCGSPKPDWASVNLCVVICKRCAGEHRGLGPSVSKVRSLKMDRKVWTEELIELFLLLGNGKANQ 81

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1622026232  676 FWAANVPPSEAVHPRSDSQERRRFLVAKYREGKYR 710
Cdd:cd17901     82 FWAANVPPSEALCPSSSSEERRHFITAKYKEGKYR 116

Ras-associating (RA) domain found in Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 1 (ARAP1); ARAP1, also termed Centaurin-delta-2 (Cnt-d2), is a phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3))-dependent Arf Rap-activated guanosine triphosphatase (GTPase)-activating protein (GAP) that inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome. It associates with the Cbl-interacting protein of 85 kDa (CIN85), regulates endocytic trafficking of the EGFR, and thus affects ubiquitination of EGFR. It also regulates the ring size of circular dorsal ruffles through Arf1 and Arf5. ARAP1 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 1622026232 1231 AGDFICTVYLEEKKTEAEQHIKIPATMTAEELTFEILDRRKIVMKEKEFWSCFEVNEREEAERPLHYSEKVLPILHSLGK 1310
Cdd:cd17226      1 SPDFICTVYLEEKKEGSEQHVQVPASMTAEELTFEILDRRNIHTREKDYWSCFEVNEREEAERPLHFSEKVLPIFHSLGS 80

                           90
                   ....*....|...
gi 1622026232 1311 DSYLVVKKQLSME 1323
Cdd:cd17226     81 DSHLVVKKHCSME 93

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 2; 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. ARAP2 localizes to the cell periphery and on focal adhesions composed of paxillin and vinculin, and functions downstream of RhoA to regulate focal adhesion dynamics. ARAP2 is a PI(3,4,5)P3-dependent Arf6 GAP that binds RhoA-GTP, but it lacks the predicted catalytic arginine in the RhoGAP domain and does not have RhoGAP activity. ARAP2 reduces Rac1oGTP levels by reducing Arf6oGTP levels through GAP activity. AGAP2 also binds to and regulates focal adhesion kinase (FAK). Thus, ARAP2 signals through Arf6 and Rac1 to control focal adhesion morphology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232  590 EALSNFEVAERIWKVEENCFCADCGSPKPDWGSINLCVVICKRCAGEHRGLGPNVTKVRSLKMDKKVWTEELIELFLQIG 669
Cdd:cd08856      1 ETLSDYEVAEKIWFNESNRSCADCKAPDPDWASINLCVVICKKCAGQHRSLGPKDSKVRSLKMDASIWSNELIELFIVVG 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|.
gi 1622026232  670 NAVANQFWAANVPPSEAVHPRSDSQERRRFLVAKYREGKYR 710
Cdd:cd08856     81 NKPANLFWAANLFSEEDLHMDSDVEQRTPFITQKYKEGKFR 121

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 1622026232  1027 DVPIIVDRCIDYITQCGLTSEGIYRKSGQNSKTTGLLEILRKDARRVrLKEGEHQVDDVANTLKRFFRDVEDGLFTKDSS 1106
Cdd:smart00324    2 PIPIIVEKCIEYLEKRGLDTEGIYRVSGSKSRVKELRDAFDSGPDPD-LDLSEYDVHDVAGLLKLFLRELPEPLITYELY 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622026232  1107 PAWLKATgkAIEDDKEKVGRYRKLLSSLPAVNRATVKALINHLYRVQCFSDMNQMTTHNLAIVFGPTLFQTDGKDYKA-- 1184
Cdd:smart00324   81 EEFIEAA--KLEDETERLRALRELLSLLPPANRATLRYLLAHLNRVAEHSEENKMTARNLAIVFGPTLLRPPDGEVASlk 158

                           170
                    ....*....|....
gi 1622026232  1185 -----GRVVEDLIR 1193
Cdd:smart00324  159 dirhqNTVIEFLIE 172

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 1622026232  497 SFDSVDKSGLLELRGFKNKLYVVVAGEKVFLYKNAEEFRLGIGITYIEMNVGNVKDVDRRGFDLTTPYRIFSFIAESDQE 576
Cdd:cd13254      2 RKPNPDKCGYLELRGYKAKVYAALMGDEVWLYKNEQDFRLGIGITVIEMNGANVKDVDRRSFDLTTPYRSFSFTAESEHE 81

                   ....*....
gi 1622026232  577 KEEWVEAMQ 585
Cdd:cd13254     82 KQEWIEAVQ 90

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 1622026232  599 ERIWKVEENCFCADCGSPKPDWGSINLCVVICKRCAGEHRGLGPNVTKVRSLKMDKkvWTEELIELFLQIGNAVANQFWA 678
Cdd:cd08204      2 EELLKLPGNKVCADCGAPDPRWASINLGVFICIRCSGIHRSLGVHISKVRSLTLDS--WTPEQVELMKAIGNARANAYYE 79

                           90       100
                   ....*....|....*....|....*..
gi 1622026232  679 ANVPPS-EAVHPRSDSQERRRFLVAKY 704
Cdd:cd08204     80 ANLPPGfKKPTPDSSDEEREQFIRAKY 106

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 1622026232  370 IKAGWLDKNPPQGttllthrapqltvfsgsRSYIYQKRWVKLDSDNLRYFDNEKDVYSKRLIPICCITRVASIGDQKFEV 449
Cdd:cd13253      1 IKSGYLDKQGGQG-----------------NNKGFQKRWVVFDGLSLRYFDSEKDAYSKRIIPLSAISTVRAVGDNKFEL 63

                           90       100       110
                   ....*....|....*....|....*....|.
gi 1622026232  450 ITNNRTFAFRAESDADRNEWIRALQKVVDEK 480
Cdd:cd13253     64 VTTNRTFVFRAESDDERNLWCSTLQAAISEY 94