Sec7 domain; The Sec7 domain is a guanine-nucleotide-exchange-factor (GEF) for the pfam00025 family.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553   661 RKRQYRVGLNLFNKKPEKGITYLIRRGFLENTPQGVARFLITRKGLSRQMIGEYLGNLqNQFNMAVLSCFAMELDLSGRQ 740
Cdd:pfam01369    1 RKKLLREGIEKFNKKPKKGIEYLIEKGFIEDDPESIAKFLFETPGLDKKAIGEYLGKP-DEFNIEVLKAFVDLFDFKGLR 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553   741 VDVALRKFQAYFRMPGEAQKIERLMEIFSQRYCECNADIVgrlRSSDTIFVLAFAIIMLNTDLHTPNLKpeRRMRVEDFI 820
Cdd:pfam01369   80 IDEALRLFLESFRLPGEAQKIDRIMEAFAERYYEQNPGVF---ANADAAYVLAYSIIMLNTDLHNPNVK--KKMTLEDFI 154

                          170       180
                   ....*....|....*....|....*....
gi 281366553   821 KNLRGIDDCHDIDKDMLMGIYDRVKSDEF 849
Cdd:pfam01369  155 RNLRGINDGKDFPDEYLEEIYDSIKKNEI 183

Sec7 domain; The Sec7 domain is a guanine-nucleotide-exchange-factor (GEF) for the pfam00025 family.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553   661 RKRQYRVGLNLFNKKPEKGITYLIRRGFLENTPQGVARFLITRKGLSRQMIGEYLGNLqNQFNMAVLSCFAMELDLSGRQ 740
Cdd:pfam01369    1 RKKLLREGIEKFNKKPKKGIEYLIEKGFIEDDPESIAKFLFETPGLDKKAIGEYLGKP-DEFNIEVLKAFVDLFDFKGLR 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553   741 VDVALRKFQAYFRMPGEAQKIERLMEIFSQRYCECNADIVgrlRSSDTIFVLAFAIIMLNTDLHTPNLKpeRRMRVEDFI 820
Cdd:pfam01369   80 IDEALRLFLESFRLPGEAQKIDRIMEAFAERYYEQNPGVF---ANADAAYVLAYSIIMLNTDLHNPNVK--KKMTLEDFI 154

                          170       180
                   ....*....|....*....|....*....
gi 281366553   821 KNLRGIDDCHDIDKDMLMGIYDRVKSDEF 849
Cdd:pfam01369  155 RNLRGINDGKDFPDEYLEEIYDSIKKNEI 183

IQ motif and SEC7 domain-containing protein family Pleckstrin homology domain; The IQSEC (also called BRAG/Brefeldin A-resistant Arf-gunanine nucleotide exchange factor) family are a subset of Arf GEFs that have been shown to activate Arf6, which acts in the endocytic pathway to control the trafficking of a subset of cargo proteins including integrins and have key roles in the function and organization of distinct excitatory and inhibitory synapses in the retina. The family consists of 3 members: IQSEC1 (also called BRAG2/GEP100), IQSEC2 (also called BRAG1), and IQSEC3 (also called SynArfGEF, BRAG3, or KIAA1110). IQSEC1 interacts with clathrin and modulates cell adhesion by regulating integrin surface expression and in addition to Arf6, it also activates the class II Arfs, Arf4 and Arf5. Mutations in IQSEC2 cause non-syndromic X-linked intellectual disability as well as reduced activation of Arf substrates (Arf1, Arf6). IQSEC3 regulates Arf6 at inhibitory synapses and associates with the dystrophin-associated glycoprotein complex and S-SCAM. These members contains a IQ domain that may bind calmodulin, a PH domain that is thought to mediate membrane localization by binding of phosphoinositides, and a SEC7 domain that can promote GEF activity on ARF. 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 281366553  876 PHRRLVCYCRLYEIPDVNKKERPGVHQREVFLFNDLLVITKIFSKKKTSVTYTFRNSFPLCGTVVTLLDMPNYPFCIQLS 955
Cdd:cd13318     1 PHRRLVCYCRLYEVPDPNKREKPGLHQREVFLFNDLLVVTKIFSKKKSSVTYSFRQSFSLLGMQVLLFETSHYPFGIRLT 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 281366553  956 QKVDGKILITFNARNEHDRCKFAEDLKESISEMDEMESLRIEAELERQ 1003
Cdd:cd13318    81 SPLDNKVLITFNARNESDRKKFVEDLRESILEVNEMESLRIEEELEKQ 128

Sec7 domain; Domain named after the S. cerevisiae SEC7 gene product, which is required for proper protein transport through the Golgi. The domain facilitates guanine nucleotide exchange on the small GTPases, ARFs (ADP ribosylation factors).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553    661 RKRQYRVGLNLFNKKPEKGITYLIRRGFLEN-TPQGVARFLITRKGLSRQMIGEYLGNlQNQFNMAVLSCFAMELDLSGR 739
Cdd:smart00222    4 RKKLLSEGIVKFNDKPKKGIQSLQEKGFLANeDPQDVADFLSKNEGLNKKAIGDYLGE-HDEFNRLVLHAFVDLFDFSAK 82

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553    740 QVDVALRKFQAYFRMPGEAQKIERLMEIFSQRYCECNADiVGRLRSSDTIFVLAFAIIMLNTDLHTPNLKpeRRMRVEDF 819
Cdd:smart00222   83 DLDQALREFLESFRLPGEAQKIDRLLEAFSSRYCECNPG-VFSKANADAAYTLAYSLIMLNTDLHNPNVK--KKMTLEDF 159

                           170       180       190
                    ....*....|....*....|....*....|
gi 281366553    820 IKNLRGIDDCHDIDKDMLMGIYDRVKSDEF 849
Cdd:smart00222  160 IKNVRGSNDGEDLPREFLEELYDSIKNNEI 189

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 281366553    886 LYEIPDVNKKERpgvHQREVFLFNDLLVITKifsKKKTSVTYTFRNSFPLCGTVVTLL---DMPNYPFCIQLsqKVDGKI 962
Cdd:smart00233    7 LYKKSGGGKKSW---KKRYFVLFNSTLLYYK---SKKDKKSYKPKGSIDLSGCTVREApdpDSSKKPHCFEI--KTSDRK 78

                            90       100
                    ....*....|....*....|....
gi 281366553    963 LITFNARNEHDRCKFAEDLKESIS 986
Cdd:smart00233   79 TLLLQAESEEEREKWVEALRKAIA 102

Sec7 domain; The Sec7 domain is a guanine-nucleotide-exchange-factor (GEF) for the pfam00025 family.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553   661 RKRQYRVGLNLFNKKPEKGITYLIRRGFLENTPQGVARFLITRKGLSRQMIGEYLGNLqNQFNMAVLSCFAMELDLSGRQ 740
Cdd:pfam01369    1 RKKLLREGIEKFNKKPKKGIEYLIEKGFIEDDPESIAKFLFETPGLDKKAIGEYLGKP-DEFNIEVLKAFVDLFDFKGLR 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553   741 VDVALRKFQAYFRMPGEAQKIERLMEIFSQRYCECNADIVgrlRSSDTIFVLAFAIIMLNTDLHTPNLKpeRRMRVEDFI 820
Cdd:pfam01369   80 IDEALRLFLESFRLPGEAQKIDRIMEAFAERYYEQNPGVF---ANADAAYVLAYSIIMLNTDLHNPNVK--KKMTLEDFI 154

                          170       180
                   ....*....|....*....|....*....
gi 281366553   821 KNLRGIDDCHDIDKDMLMGIYDRVKSDEF 849
Cdd:pfam01369  155 RNLRGINDGKDFPDEYLEEIYDSIKKNEI 183

IQ motif and SEC7 domain-containing protein family Pleckstrin homology domain; The IQSEC (also called BRAG/Brefeldin A-resistant Arf-gunanine nucleotide exchange factor) family are a subset of Arf GEFs that have been shown to activate Arf6, which acts in the endocytic pathway to control the trafficking of a subset of cargo proteins including integrins and have key roles in the function and organization of distinct excitatory and inhibitory synapses in the retina. The family consists of 3 members: IQSEC1 (also called BRAG2/GEP100), IQSEC2 (also called BRAG1), and IQSEC3 (also called SynArfGEF, BRAG3, or KIAA1110). IQSEC1 interacts with clathrin and modulates cell adhesion by regulating integrin surface expression and in addition to Arf6, it also activates the class II Arfs, Arf4 and Arf5. Mutations in IQSEC2 cause non-syndromic X-linked intellectual disability as well as reduced activation of Arf substrates (Arf1, Arf6). IQSEC3 regulates Arf6 at inhibitory synapses and associates with the dystrophin-associated glycoprotein complex and S-SCAM. These members contains a IQ domain that may bind calmodulin, a PH domain that is thought to mediate membrane localization by binding of phosphoinositides, and a SEC7 domain that can promote GEF activity on ARF. 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 281366553  876 PHRRLVCYCRLYEIPDVNKKERPGVHQREVFLFNDLLVITKIFSKKKTSVTYTFRNSFPLCGTVVTLLDMPNYPFCIQLS 955
Cdd:cd13318     1 PHRRLVCYCRLYEVPDPNKREKPGLHQREVFLFNDLLVVTKIFSKKKSSVTYSFRQSFSLLGMQVLLFETSHYPFGIRLT 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 281366553  956 QKVDGKILITFNARNEHDRCKFAEDLKESISEMDEMESLRIEAELERQ 1003
Cdd:cd13318    81 SPLDNKVLITFNARNESDRKKFVEDLRESILEVNEMESLRIEEELEKQ 128

Sec7 domain; Domain named after the S. cerevisiae SEC7 gene product, which is required for proper protein transport through the Golgi. The domain facilitates guanine nucleotide exchange on the small GTPases, ARFs (ADP ribosylation factors).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553    661 RKRQYRVGLNLFNKKPEKGITYLIRRGFLEN-TPQGVARFLITRKGLSRQMIGEYLGNlQNQFNMAVLSCFAMELDLSGR 739
Cdd:smart00222    4 RKKLLSEGIVKFNDKPKKGIQSLQEKGFLANeDPQDVADFLSKNEGLNKKAIGDYLGE-HDEFNRLVLHAFVDLFDFSAK 82

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553    740 QVDVALRKFQAYFRMPGEAQKIERLMEIFSQRYCECNADiVGRLRSSDTIFVLAFAIIMLNTDLHTPNLKpeRRMRVEDF 819
Cdd:smart00222   83 DLDQALREFLESFRLPGEAQKIDRLLEAFSSRYCECNPG-VFSKANADAAYTLAYSLIMLNTDLHNPNVK--KKMTLEDF 159

                           170       180       190
                    ....*....|....*....|....*....|
gi 281366553    820 IKNLRGIDDCHDIDKDMLMGIYDRVKSDEF 849
Cdd:smart00222  160 IKNVRGSNDGEDLPREFLEELYDSIKNNEI 189

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6, N-terminal Pleckstrin Homology (PH) domain; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH domain. 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 281366553  872 NLALPHRRLVcycRLYEIPDVNKKErpgVHQREVFLFNDLLVITkifSKKKTSVTYTFRNSFPLCGTVVTLLDMPNYPFC 951
Cdd:cd13389     6 NIVKPGRKLI---KEGELMKVSRKE---MQPRYFFLFNDCLLYT---TPVQSSGMLKLNNELPLSGMKVKLPEDEEYSNE 76

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 281366553  952 IQLSQKVDGKILItfnARNEHDRCKFAEDLKESISEM 988
Cdd:cd13389    77 FQIISTKRSFTLI---ASSEEERDEWVKALSRAIEEH 110

FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 1; Members here include FARP1 (also called Chondrocyte-derived ezrin-like protein; PH domain-containing family C member 2), FARP2 (also called FIR/FERM domain including RhoGEF; FGD1-related Cdc42-GEF/FRG), and FARP6 (also called Zinc finger FYVE domain-containing protein 24). They are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. Little is known about FARP1 and FARP6, though FARP1 has increased expression in differentiated chondrocytes. FARP2 is thought to regulate neurite remodeling by mediating the signaling pathways from membrane proteins to Rac. It is found in brain, lung, and testis, as well as embryonic hippocampal and cortical neurons. FARP1 and FARP2 are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. FARP6 is composed of Dbl-homology (DH), and two C-terminal PH domains separated by a FYVE domain. This hierarchy contains the first PH repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281366553  873 LALPHRRLVCYCRLYeipdvnKKERPGVHQREVFLFNDLLvitkIFSKKKTSVTYTFR--NSFPLCGTVVTLLD---MPN 947
Cdd:cd01220     1 LVQPGREFIREGCLQ------KLSKKGLQQRMFFLFSDVL----LYTSRSPTPSLQFKvhGQLPLRGLMVEESEpewGVA 70

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 281366553  948 YPFCIQLSQKVdgkilITFNARNEHDRCKFAEDLKESISEMDE 990
Cdd:cd01220    71 HCFTIYGGNRA-----LTVAASSEEEKERWLEDLQRAIDAAKK 108

Pleckstrin homology (PH) domain; 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 281366553  901 HQREVFLFNDLLVitkiFSKKKTSVTYTFRNSFPLCGTV-VTLLDMPNYPFCIQLsqKVDGKILITFNARNEHDRCKFAE 979
Cdd:cd00821    17 KKRWFVLFEGVLL----YYKSKKDSSYKPKGSIPLSGILeVEEVSPKERPHCFEL--VTPDGRTYYLQADSEEERQEWLK 90

                  ..
gi 281366553  980 DL 981
Cdd:cd00821    91 AL 92