Centaurin gamma (CENTG) GTPase; The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 128 LKVGIVGNLSSGKSALVHRYLTGTYVQEESPEGGRFKKEIVVDGQSYLLLIRDEGGPPELQFAAWVDAVVFVFSLEDEIS 207
Cdd:cd04103     1 LKLGIVGNLRSGKSALVHRYLTGSYVQLESPEGGRFKKEVLVDGQSHLLLIRDEGGAPDAQFAGWVDAVIFVFSLEDEAS 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1173708348 208 FQTVYNYFLRLCSFRNASEVPMVLVGTQDAISAANPRVIDDSRARKLSTDLKRCTYYETCATYGLNVERVFQDVAQKV 285
Cdd:cd04103    81 FQTVYRLYHQLSSYRNISEIPLILVGTQDAISASNPRVIDDARARQLCADMKRCSYYETCATYGLNVERVFQEAAQKI 158

Arf-GAP with GTPase, ANK repeat and PH domain-containing protein Pleckstrin homology (PH) domain; AGAP (also called centaurin gamma; PIKE/Phosphatidylinositol-3-kinase enhancer) reside mainly in the nucleus and are known to activate phosphoinositide 3-kinase, a key regulator of cell proliferation, motility and vesicular trafficking. There are 3 isoforms of AGAP (PIKE-A, PIKE-L, and PIKE-S) the longest of which PIKE-L consists of N-terminal proline rich domains (PRDs), followed by a GTPase domain, a split PH domain (PHN and PHC), an ArfGAP domain and two ankyrin repeats. PIKE-S terminates after the PHN domain and PIKE-A is missing the PRD region. Centaurin binds phosphatidlyinositol (3,4,5)P3. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 401 RAIPIKQGILLKRSGKSLNKEWKKKYVTLCDNGLLTYHPSLHDYMQNIHGKEIDLLRTTVKVPGKRLPRATPATApgtsp 480
Cdd:cd01250     1 RAIPIKQGYLYKRSSKSLNKEWKKKYVTLCDDGRLTYHPSLHDYMENVHGKEIDLLRTTVKVPGKRPPRASSKSA----- 75

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1173708348 481 ranglsversntqlgggteaeesFEFVVVSLTGQTWHFEASTAEERELWVQSVQAQILASLQ 542
Cdd:cd01250    76 -----------------------FEFIIVSLDGKQWHFEAASSEERDEWVQAIEQQILASLQ 114

Centaurin gamma (CENTG) GTPase; The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 128 LKVGIVGNLSSGKSALVHRYLTGTYVQEESPEGGRFKKEIVVDGQSYLLLIRDEGGPPELQFAAWVDAVVFVFSLEDEIS 207
Cdd:cd04103     1 LKLGIVGNLRSGKSALVHRYLTGSYVQLESPEGGRFKKEVLVDGQSHLLLIRDEGGAPDAQFAGWVDAVIFVFSLEDEAS 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1173708348 208 FQTVYNYFLRLCSFRNASEVPMVLVGTQDAISAANPRVIDDSRARKLSTDLKRCTYYETCATYGLNVERVFQDVAQKV 285
Cdd:cd04103    81 FQTVYRLYHQLSSYRNISEIPLILVGTQDAISASNPRVIDDARARQLCADMKRCSYYETCATYGLNVERVFQEAAQKI 158

Arf-GAP with GTPase, ANK repeat and PH domain-containing protein Pleckstrin homology (PH) domain; AGAP (also called centaurin gamma; PIKE/Phosphatidylinositol-3-kinase enhancer) reside mainly in the nucleus and are known to activate phosphoinositide 3-kinase, a key regulator of cell proliferation, motility and vesicular trafficking. There are 3 isoforms of AGAP (PIKE-A, PIKE-L, and PIKE-S) the longest of which PIKE-L consists of N-terminal proline rich domains (PRDs), followed by a GTPase domain, a split PH domain (PHN and PHC), an ArfGAP domain and two ankyrin repeats. PIKE-S terminates after the PHN domain and PIKE-A is missing the PRD region. Centaurin binds phosphatidlyinositol (3,4,5)P3. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 401 RAIPIKQGILLKRSGKSLNKEWKKKYVTLCDNGLLTYHPSLHDYMQNIHGKEIDLLRTTVKVPGKRLPRATPATApgtsp 480
Cdd:cd01250     1 RAIPIKQGYLYKRSSKSLNKEWKKKYVTLCDDGRLTYHPSLHDYMENVHGKEIDLLRTTVKVPGKRPPRASSKSA----- 75

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1173708348 481 ranglsversntqlgggteaeesFEFVVVSLTGQTWHFEASTAEERELWVQSVQAQILASLQ 542
Cdd:cd01250    76 -----------------------FEFIIVSLDGKQWHFEAASSEERDEWVQAIEQQILASLQ 114

Putative GTP-ase activating proteins for the small GTPase, ARF; Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348  563 QAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSVWEGA 642
Cdd:smart00105   2 KLLRSIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSLGVHISKVRSLTLDTWTEEELRLLQKGGNENANSIWESN 81

                           90       100       110
                   ....*....|....*....|....*....|....*...
gi 1173708348  643 LG-GYSKPGPDACREEKERWIRAKYEQKLFLAPLPSSD 679
Cdd:smart00105  82 LDdFSLKPPDDDDQQKYESFIAAKYEEKLFVPPESAEE 119

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 555 NQNAALAV-QAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNA 633
Cdd:PLN03114    5 NLNDKISVfKKLKAKSDNKICFDCNAKNPTWASVTYGIFLCIDCSAVHRSLGVHISFVRSTNLDSWSSEQLKMMIYGGNN 84

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1173708348 634 LANSVWEG---ALGG-----YSKPGPDACREEKERWI-RAKYEQKLFLAPLP--SSDVPLG 683
Cdd:PLN03114   85 RAQVFFKQygwSDGGkteakYTSRAADLYKQILAKEVaKSKAEEELDLPPSPpdSTQVPNG 145

Ras family; Includes sub-families Ras, Rab, Rac, Ral, Ran, Rap Ypt1 and more. Shares P-loop motif with GTP_EFTU, arf and myosin_head. See pfam00009 pfam00025, pfam00063. As regards Rab GTPases, these are important regulators of vesicle formation, motility and fusion. They share a fold in common with all Ras GTPases: this is a six-stranded beta-sheet surrounded by five alpha-helices.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 129 KVGIVGNLSSGKSALVHRYLTGTYVQE-ESPEGGRFK-KEIVVDGQSYLLLIRDEGGPPElqFAA-----WVDAVVF--V 199
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLIRFTQNKFPEEyIPTIGVDFYtKTIEVDGKTVKLQIWDTAGQER--FRAlrplyYRGADGFllV 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 200 FSLEDEISFQTVYNYF---LRLCSfrnaSEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKrCTYYETCATYGLNVER 276
Cdd:pfam00071  79 YDITSRDSFENVKKWVeeiLRHAD----ENVPIVLVGNK--CDLEDQRVVSTEEGEALAKELG-LPFMETSAKTNENVEE 151

                  ....*....
gi 1173708348 277 VFQDVAQKV 285
Cdd:pfam00071 152 AFEELAREI 160

GTPase SAR1 family domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 127 ELKVGIVGNLSSGKSALVHRYLTGTYVQEE--SPEG-GRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWV---DA 195
Cdd:COG1100     3 EKKIVVVGTGGVGKTSLVNRLVGDIFSLEKylSTNGvTIDKKELKLDGLDVDLVIWDTPGQDEFretrqFYARQLtgaSL 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 196 VVFVFSLEDEISFQTVYNYFLRLcsFRNASEVPMVLVGTQ-DAISaaNPRVIDDSRARKLSTDLKRCTYYETCATYGLNV 274
Cdd:COG1100    83 YLFVVDGTREETLQSLYELLESL--RRLGKKSPIILVLNKiDLYD--EEEIEDEERLKEALSEDNIVEVVATSAKTGEGV 158

                  ....*....
gi 1173708348 275 ERVFQDVAQ 283
Cdd:COG1100   159 EELFAALAE 167

Ankyrin repeats (3 copies);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 686 LLRAVVEDDLRLLVMLLAHGSKEEVNetygDGDGRTALHLSSAMANVVFTQLLIWYgVDVRSRDaRGLTPLAYARRAGSQ 765
Cdd:pfam12796   1 LHLAAKNGNLELVKLLLENGADANLQ----DKNGRTALHLAAKNGHLEIVKLLLEH-ADVNLKD-NGRTALHYAARSGHL 74

                          90
                  ....*....|.
gi 1173708348 766 ECADILIQHGC 776
Cdd:pfam12796  75 EIVKLLLEKGA 85

Ras-like protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 127 ELKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWVDAVVFVF 200
Cdd:PTZ00369    5 EYKLVVVGGGGVGKSALTIQFIQNHFIDEYDPTiEDSYRKQCVIDEETCLLDILDTAGQEEYsamrdQYMRTGQGFLCVY 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 201 SLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQDAISaaNPRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVFQD 280
Cdd:PTZ00369   85 SITSRSSFEEIASFREQILRVKDKDRVPMILVGNKCDLD--SERQVSTGEGQELAKSFG-IPFLETSAKQRVNVDEAFYE 161

                  ....*
gi 1173708348 281 VAQKV 285
Cdd:PTZ00369  162 LVREI 166

Transient Receptor Potential channel, Vanilloid subfamily (TRPV), types 5 and 6; TRPV5 and TRPV6 (TRPV5/6) are two homologous members within the vanilloid subfamily of the transient receptor potential (TRP) family. TRPV5 and TRPV6 show only 30-40% homology with other members of the TRP family and have unique properties that differentiates them from other TRP channels. They mediate calcium uptake in epithelia and their expression is dramatically increased in numerous types of cancer. The structure of TRPV5/6 shows the typical topology features of all TRP family members, such as six transmembrane regions, a short hydrophobic stretch between transmembrane segments 5 and 6, which is predicted to form the Ca2+ pore, and large intracellular N- and C-terminal domains. The N-terminal domain of TRPV5/6 contains three ankyrin repeats. This structural element is present in several proteins and plays a role in protein-protein interactions. The N- and C-terminal tails of TRPV5/6 each contain an internal PDZ motif which can function as part of a molecular scaffold via interaction with PDZ-domain containing proteins. A major difference between the properties of TRPV5 and TRPV6 is in their tissue distribution: TRPV5 is predominantly expressed in the distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, with limited expression in extrarenal tissues. In contrast, TRPV6 has a broader expression pattern such as expression in the intestine, kidney, placenta, epididymis, exocrine tissues, and a few other tissues.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 676 PSSDV----PLGQQLLRAVVEDDLRLLVMLLAHGSKEEVNE--TYGDGDGRTALHLSSAMANVVFTQLLIWYGVDVRSRD 749
Cdd:cd22192    40 PSCDLfqrgALGETALHVAALYDNLEAAVVLMEAAPELVNEpmTSDLYQGETALHIAVVNQNLNLVRELIARGADVVSPR 119

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1173708348 750 ARGLT--------------PLAYARRAGSQECADILIQHG 775
Cdd:cd22192   120 ATGTFfrpgpknliyygehPLSFAACVGNEEIVRLLIEHG 159

Centaurin gamma (CENTG) GTPase; The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 128 LKVGIVGNLSSGKSALVHRYLTGTYVQEESPEGGRFKKEIVVDGQSYLLLIRDEGGPPELQFAAWVDAVVFVFSLEDEIS 207
Cdd:cd04103     1 LKLGIVGNLRSGKSALVHRYLTGSYVQLESPEGGRFKKEVLVDGQSHLLLIRDEGGAPDAQFAGWVDAVIFVFSLEDEAS 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1173708348 208 FQTVYNYFLRLCSFRNASEVPMVLVGTQDAISAANPRVIDDSRARKLSTDLKRCTYYETCATYGLNVERVFQDVAQKV 285
Cdd:cd04103    81 FQTVYRLYHQLSSYRNISEIPLILVGTQDAISASNPRVIDDARARQLCADMKRCSYYETCATYGLNVERVFQEAAQKI 158

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 1173708348 561 AVQAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSVWE 640
Cdd:cd08836     2 ALQAIRNVRGNDHCVDCGAPNPDWASLNLGALMCIECSGIHRNLGTHISRVRSLDLDDWPVELLKVMSAIGNDLANSVWE 81

                          90       100
                  ....*....|....*....|....*..
gi 1173708348 641 GALGGYSKPGPDACREEKERWIRAKYE 667
Cdd:cd08836    82 GNTQGRTKPTPDSSREEKERWIRAKYE 108

ArfGAP with GTPase domain, ANK repeat and PH domain 2; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 559 ALAVQAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSV 638
Cdd:cd08853     1 AMALQSIRNMRGNSHCVDCETQNPKWASLNLGVLMCIECSGIHRNLGTHLSRVRSLDLDDWPVELRKVMSSIGNELANSI 80

                          90       100
                  ....*....|....*....|....*....
gi 1173708348 639 WEGALGGYSKPGPDACREEKERWIRAKYE 667
Cdd:cd08853    81 WEGSSQGQTKPSSDSTREEKERWIRAKYE 109

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 1173708348 562 VQAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSVWEG 641
Cdd:cd08204     1 LEELLKLPGNKVCADCGAPDPRWASINLGVFICIRCSGIHRSLGVHISKVRSLTLDSWTPEQVELMKAIGNARANAYYEA 80

                          90       100
                  ....*....|....*....|....*.
gi 1173708348 642 ALG-GYSKPGPDACREEKERWIRAKY 666
Cdd:cd08204    81 NLPpGFKKPTPDSSDEEREQFIRAKY 106

Putative GTP-ase activating proteins for the small GTPase, ARF; Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348  563 QAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSVWEGA 642
Cdd:smart00105   2 KLLRSIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSLGVHISKVRSLTLDTWTEEELRLLQKGGNENANSIWESN 81

                           90       100       110
                   ....*....|....*....|....*....|....*...
gi 1173708348  643 LG-GYSKPGPDACREEKERWIRAKYEQKLFLAPLPSSD 679
Cdd:smart00105  82 LDdFSLKPPDDDDQQKYESFIAAKYEEKLFVPPESAEE 119

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 562 VQAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSVWEG 641
Cdd:cd08850     4 LQRVQSIAGNDQCCDCGQPDPRWASINLGILLCIECSGIHRSLGVHCSKVRSLTLDSWEPELLKLMCELGNSTVNQIYEA 83

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1173708348 642 AL--GGYSKPGPDACREEKERWIRAKYEQKLFL 672
Cdd:cd08850    84 QCeeLGLKKPTASSSRQDKEAWIKAKYVEKKFL 116

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 561 AVQAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSVWE 640
Cdd:cd08851     3 ALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRIYE 82

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1173708348 641 GALG--GYSKPGPDACREEKERWIRAKYEQKLFL 672
Cdd:cd08851    83 ARVEkmGAKKPQPGGQRQEKEAYIRAKYVERKFV 116

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 562 VQAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSVWEG 641
Cdd:cd08834     6 IAEVKRLPGNDVCCDCGSPDPTWLSTNLGILTCIECSGVHRELGVHVSRIQSLTLDNLGTSELLLARNLGNEGFNEIMEA 85

                          90       100       110
                  ....*....|....*....|....*....|
gi 1173708348 642 ALGGYSKPGPDACREEKERWIRAKYEQKLF 671
Cdd:cd08834    86 NLPPGYKPTPNSDMEERKDFIRAKYVEKKF 115

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 1173708348 562 VQAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDD--WPPELLAVMTAMGNALANSVW 639
Cdd:cd08837     4 AEKIWSNPANRFCADCGAPDPDWASINLCVVICKQCAGEHRSLGSNISKVRSLKMDTkvWTEELVELFLKLGNDRANRFW 83

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1173708348 640 EGALggysKPG----PDACREEKERWIRAKYEQKLF 671
Cdd:cd08837    84 AANL----PPSealhPDADSEQRREFITAKYREGKY 115

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 1173708348 554 GNQNAALAVQAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNA 633
Cdd:COG5347     3 TKSEDRKLLKLLKSDSSNKKCADCGAPNPTWASVNLGVFLCIDCAGVHRSLGVHISKVKSLTLDNWTEEELRRMEVGGNS 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 634 LANSVWEG----ALGGYSKPGPDAcrEEKERWIRAKYEQKLFL----APLPSSDVPLGQQLLRAVVEDDLRLL-----VM 700
Cdd:COG5347    83 NANRFYEKnlldQLLLPIKAKYDS--SVAKKYIRKKYELKKFIddssSPSDFSSFSASSTRTVDSVDDRLDSEsqsrsSS 160

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....
gi 1173708348 701 LLAHGSKEEVNETYGDGDGRTALHL------SSAMANVVFTQLL 738
Cdd:COG5347   161 ASLGNSNRPDDELNVESFQSTGSKPrsltstKSNKDNLLNSELL 204

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1173708348 563 QAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALAN 636
Cdd:cd08959     6 KKLRSKPENKVCFDCGAKNPQWASVTYGIFICLDCSGVHRGLGVHISFVRSTTMDKWTEEQLRKMKVGGNANAR 79

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1173708348 562 VQAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSVWE 640
Cdd:cd08831     6 FKKLRSKPENKVCFDCGAKNPTWASVTFGVFLCLDCSGVHRSLGVHISFVRSTNLDSWTPEQLRRMKVGGNAKAREFFK 84

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 1173708348 563 QAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDD--WPPELLAVMTAMGNALANSVWE 640
Cdd:cd17901     5 EKIWSVESNRFCADCGSPKPDWASVNLCVVICKRCAGEHRGLGPSVSKVRSLKMDRkvWTEELIELFLLLGNGKANQFWA 84

                          90       100
                  ....*....|....*....|....*...
gi 1173708348 641 GALGGYSKPGPDACREEKERWIRAKYEQ 668
Cdd:cd17901    85 ANVPPSEALCPSSSSEERRHFITAKYKE 112

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 560 LAVQAVRTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSVW 639
Cdd:cd17900     4 LLIAEVKSRPGNSQCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVRYSRIQSLTLDLLSTSELLLAVSMGNTRFNEVM 83

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1173708348 640 EGAL--GGYSKPGPDACREEKERWIRAKYEQKLF 671
Cdd:cd17900    84 EATLpaHGGPKPSAESDMGTRKDYIMAKYVEHRF 117

GIT2 GTPase activating protein for Arf; The GIT (G-protein coupled receptor kinase-interacting protein) subfamily includes GIT1 and GIT2, which have three ANK repeats, a Spa-homology domain (SHD), a coiled-coil domain and a C-terminal paxillin-binding site (PBS). The GIT1/2 proteins are GTPase-activating proteins that function as an inactivator of Arf signaling, and interact with the PIX/Cool family of Rac/Cdc42 guanine nucleotide exchange factors (GEFs). Unlike other ArfGAPs, GIT and PIX (Pak-interacting exchange factor) proteins are tightly associated to form an oligomeric complex that acts as a scaffold and signal integrator that can be recruited for multiple signaling pathways. The GIT/PIX complex functions as a signaling scaffold by binding to specific protein partners. As a result, the complex is transported to specific cellular locations. For instance, the GIT partners paxillin or integrin-alpha4 (to focal adhesions), piccolo and liprin-alpha (to synapses), and the beta-PIX partner Scribble (to epithelial cell-cell contacts and synapses). Moreover, the GIT/PIT complex functions to integrate signals from multiple GTP-binding protein and protein kinase pathways to regulate the actin cytoskeleton and thus cell polarity, adhesion and migration.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1173708348 566 RTVRGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDDWPPELLAVMTAMGNALANSVWEGAL-- 643
Cdd:cd08847     3 KRLRSSEVCADCSTSDPRWASVNRGVLICDECCSVHRSLGRHISQVRHLKHTSWPPTLLQMVQTLYNNGANSIWEHSLld 82

                          90       100
                  ....*....|....*....|....*....
gi 1173708348 644 -----GGYSKPGP-DACREEKERWIRAKY 666
Cdd:cd08847    83 pasimSGKRKANPqDKVHPNKAEFIRAKY 111

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 1173708348 569 RGNSFCIDCDAPNPDWASLNLGALMCIECSGIHRHLGAHLSRVRSLDLDD--WPPELLAVMTAMGNALANSVWEGALGGY 646
Cdd:cd17902    11 KANRFCADCHASSPDWASINLCVVICKQCAGQHRSLGSGISKVQSLKLDTsvWSNEIVQLFIVLGNDRANRFWAARLPAS 90