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 1207191405 477 RRGLIHEGALLWKTAQGsRLKDVHVLLMTDVLVFMQEKDQKYVFPTLDKPSVLCLQNLIVRDIANQQRGMFLIShSTPPE 556
Cdd:cd13393     1 RRKLIHDGCLLWKTASG-RFKDVQVLLMTDVLVFLQEKDQKYIFPTLDKPAVISLQNLIVRDIANQEKGMFLIS-AAPPE 78

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1207191405 557 MYELHAASKDDRNTWMKIIQQTVSNCPSREDFPLIETE 594
Cdd:cd13393    79 MYEVHAASRDDRNTWMRLIQQTVKTCPSREEFPLIETE 116

protein kinase C conserved region 1 (C1 domain) found in Rho guanine nucleotide exchange factor 2 (ARHGEF2) and similar proteins; ARHGEF2, also called guanine nucleotide exchange factor H1 (GEF-H1), microtubule-regulated Rho-GEF, or proliferating cell nucleolar antigen p40, acts as guanine nucleotide exchange factor (GEF) that activates Rho-GTPases by promoting the exchange of GDP for GTP. It is thought to play a role in actin cytoskeleton reorganization in different tissues since its activation induces formation of actin stress fibers. ARHGEF2 may be involved in epithelial barrier permeability, cell motility and polarization, dendritic spine morphology, antigen presentation, leukemic cell differentiation, cell cycle regulation, innate immune response, and cancer. It contains a C1 domain followed by Dbl-homology (DH) and pleckstrin-homology (PH) domains which bind and catalyze the exchange of GDP for GTP on RhoA. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1207191405  42 RYSNGHLFTSLSVSATTLCSACNKSITAKEALSCPTCNVTIHNRCRDTLANCAKMKQKQQR 102
Cdd:cd20877     1 RYTNGHLFTTITVSGTTMCSACNKSITAKEALICPTCNVTIHNRCKDTLPNCTKVKQKQQK 61

Rho guanine nucleotide exchange factor 2 Pleckstrin homology (PH) domain; ARHGEF2, also called GEF-H1, acts as guanine nucleotide exchange factor (GEF) for RhoA GTPases. It is thought to play a role in actin cytoskeleton reorganization in different tissues since its activation induces formation of actin stress fibers. ARHGEF2 contains a C1 domain followed by Dbl-homology (DH) and pleckstrin-homology (PH) domains which bind and catalyze the exchange of GDP for GTP on RhoA. 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 1207191405 477 RRGLIHEGALLWKTAQGsRLKDVHVLLMTDVLVFMQEKDQKYVFPTLDKPSVLCLQNLIVRDIANQQRGMFLIShSTPPE 556
Cdd:cd13393     1 RRKLIHDGCLLWKTASG-RFKDVQVLLMTDVLVFLQEKDQKYIFPTLDKPAVISLQNLIVRDIANQEKGMFLIS-AAPPE 78

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1207191405 557 MYELHAASKDDRNTWMKIIQQTVSNCPSREDFPLIETE 594
Cdd:cd13393    79 MYEVHAASRDDRNTWMRLIQQTVKTCPSREEFPLIETE 116

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207191405  246 VIYELIQTEFNHVRTLRIMEGVFRRGMLEEVM-MEMGVVHAIFPCLDQLLLIHTNFLSQLLQRRSNSLASnsnrnftIQK 324
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKlLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDS-------VER 73

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207191405  325 LGDILVEQfsgqnaEDMRKCYVEFCSRHLKAVKLYKELLArDKRFQQFIRRVSRGSLLRRHGVQECILLVTQRITKYPVL 404
Cdd:smart00325  74 IGDVFLKL------EEFFKIYSEYCSNHPDALELLKKLKK-NPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLL 146

                          170       180       190
                   ....*....|....*....|....*....|....
gi 1207191405  405 MQRILDNTKGNEEESKSLAQSLTLIRELLCSVDQ 438
Cdd:smart00325 147 LKELLKHTPEDHEDREDLKKALKAIKELANQVNE 180

protein kinase C conserved region 1 (C1 domain) found in Rho guanine nucleotide exchange factor 2 (ARHGEF2) and similar proteins; ARHGEF2, also called guanine nucleotide exchange factor H1 (GEF-H1), microtubule-regulated Rho-GEF, or proliferating cell nucleolar antigen p40, acts as guanine nucleotide exchange factor (GEF) that activates Rho-GTPases by promoting the exchange of GDP for GTP. It is thought to play a role in actin cytoskeleton reorganization in different tissues since its activation induces formation of actin stress fibers. ARHGEF2 may be involved in epithelial barrier permeability, cell motility and polarization, dendritic spine morphology, antigen presentation, leukemic cell differentiation, cell cycle regulation, innate immune response, and cancer. It contains a C1 domain followed by Dbl-homology (DH) and pleckstrin-homology (PH) domains which bind and catalyze the exchange of GDP for GTP on RhoA. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1207191405  42 RYSNGHLFTSLSVSATTLCSACNKSITAKEALSCPTCNVTIHNRCRDTLANCAKMKQKQQR 102
Cdd:cd20877     1 RYTNGHLFTTITVSGTTMCSACNKSITAKEALICPTCNVTIHNRCKDTLPNCTKVKQKQQK 61

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 1207191405  480 LIHEGALLWKTAQGSR-LKDVHVLLMTDVLVFMQEKDQKYVFptlDKPSVLCLQNLIVRDIANQ----QRGMFLISHSTP 554
Cdd:smart00233   1 VIKEGWLYKKSGGGKKsWKKRYFVLFNSTLLYYKSKKDKKSY---KPKGSIDLSGCTVREAPDPdsskKPHCFEIKTSDR 77

                           90       100
                   ....*....|....*....|....*.
gi 1207191405  555 pEMYELHAASKDDRNTWMKIIQQTVS 580
Cdd:smart00233  78 -KTLLLQAESEEEREKWVEALRKAIA 102

Phorbol esters/diacylglycerol binding domain (C1 domain); This domain is also known as the Protein kinase C conserved region 1 (C1) domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1207191405  47 HLFTSLSVSATTLCSACNKSI--TAKEALSCPTCNVTIHNRCRDTLANC 93
Cdd:pfam00130   1 HHFVHRNFKQPTFCDHCGEFLwgLGKQGLKCSWCKLNVHKRCHEKVPPE 49

Rho guanine nucleotide exchange factor 2 Pleckstrin homology (PH) domain; ARHGEF2, also called GEF-H1, acts as guanine nucleotide exchange factor (GEF) for RhoA GTPases. It is thought to play a role in actin cytoskeleton reorganization in different tissues since its activation induces formation of actin stress fibers. ARHGEF2 contains a C1 domain followed by Dbl-homology (DH) and pleckstrin-homology (PH) domains which bind and catalyze the exchange of GDP for GTP on RhoA. 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 1207191405 477 RRGLIHEGALLWKTAQGsRLKDVHVLLMTDVLVFMQEKDQKYVFPTLDKPSVLCLQNLIVRDIANQQRGMFLIShSTPPE 556
Cdd:cd13393     1 RRKLIHDGCLLWKTASG-RFKDVQVLLMTDVLVFLQEKDQKYIFPTLDKPAVISLQNLIVRDIANQEKGMFLIS-AAPPE 78

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1207191405 557 MYELHAASKDDRNTWMKIIQQTVSNCPSREDFPLIETE 594
Cdd:cd13393    79 MYEVHAASRDDRNTWMRLIQQTVKTCPSREEFPLIETE 116

Rho guanine nucleotide exchange factor Pleckstrin homology domain; p190RhoGEF (also called RIP2 or ARHGEF28) belongs to regulator of G-protein signaling (RGS) domain-containing RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. In addition to the Dbl homology (DH)-PH domain, p190RhoGEF contains an N-terminal C1 (Protein kinase C conserved region 1) domain. The DH-PH domains bind and catalyze the exchange of GDP for GTP on RhoA. 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 1207191405 480 LIHEGALLWKTAQGsRLKDVHVLLMTDVLVFMQEKDQKYVFPTLD-KPSVLCLQNLIVRDIANQQRGMFLISHSTP-PEM 557
Cdd:cd14680     1 LLHEGLVYWKTATG-RFKDILALLLTDVLLFLQEKDQKYIFAAVDqKPPVICLQKLIVREVANEERGMFLISASSAgPEM 79

                          90       100
                  ....*....|....*....|..
gi 1207191405 558 YELHAASKDDRNTWMKIIQQTV 579
Cdd:cd14680    80 YEIHTSSKEERNNWMRLIQEAV 101

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207191405  246 VIYELIQTEFNHVRTLRIMEGVFRRGMLEEVM-MEMGVVHAIFPCLDQLLLIHTNFLSQLLQRRSNSLASnsnrnftIQK 324
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKlLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDS-------VER 73

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207191405  325 LGDILVEQfsgqnaEDMRKCYVEFCSRHLKAVKLYKELLArDKRFQQFIRRVSRGSLLRRHGVQECILLVTQRITKYPVL 404
Cdd:smart00325  74 IGDVFLKL------EEFFKIYSEYCSNHPDALELLKKLKK-NPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLL 146

                          170       180       190
                   ....*....|....*....|....*....|....
gi 1207191405  405 MQRILDNTKGNEEESKSLAQSLTLIRELLCSVDQ 438
Cdd:smart00325 147 LKELLKHTPEDHEDREDLKKALKAIKELANQVNE 180

rho guanine nucleotide exchange factor; RhoGEFs belongs to regulator of G-protein signaling (RGS) domain-containing RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. The members here all contain Dbl homology (DH)-PH domains. In addition some members contain N-terminal C1 (Protein kinase C conserved region 1) domains, PDZ (also called DHR/Dlg homologous regions) domains, ANK (ankyrin) domains, and RGS (Regulator of G-protein signalling) domains or C-terminal ATP-synthase B subunit. The DH-PH domains bind and catalyze the exchange of GDP for GTP on RhoA. RhoGEF2/Rho guanine nucleotide exchange factor 2, p114RhoGEF/p114 Rho guanine nucleotide exchange factor, p115RhoGEF, p190RhoGEF, PRG/PDZ Rho guanine nucleotide exchange factor, RhoGEF 11, RhoGEF 12, RhoGEF 18, AKAP13/A-kinase anchoring protein 13, and LARG/Leukemia-associated Rho guanine nucleotide exchange factor are included in this CD. 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 1207191405 480 LIHEGALLWKTAQGsRLKDVHVLLMTDVLVFMQEKDQKYVFPTLD-KPSVLCLQNLIVRDIANQQRGMFLIShSTPPEMY 558
Cdd:cd15789     1 LKFEGTAWLKQARG-KTKDVLVVVLTDVLFFLQEKDQKYVFVSPDnKAGVVSLQKLLVREKAGQEKRMFLIS-ASPDGMP 78

                          90       100
                  ....*....|....*....|....
gi 1207191405 559 ELHAASKD---DRNTWMKIIQQTV 579
Cdd:cd15789    79 EMYELKVQkpkDKNTWIQTIRQAV 102

A-kinase anchoring protein 13 Pleckstrin homology (PH) domain; The Rho-specific GEF activity of AKAP13 (also called Brx-1, AKAP-Lbc, and proto-Lbc) mediates signaling downstream of G-protein coupled receptors and Toll-like receptor 2. It plays a role in cell growth, cell development and actin fiber formation. Protein kinase A (PKA) binds and phosphorylates AKAP13, regulating its Rho-GEF activity. Alternative splicing of this gene in humans has at least 3 transcript variants encoding different isoforms (i.e. proto-/onco-Lymphoid blast crisis, Lbc and breast cancer nuclear receptor-binding auxiliary protein, Brx) containing a dbl oncogene homology (DH) domain and PH domain which are required for full transforming activity. The DH domain is associated with guanine nucleotide exchange activation while the PH domain has multiple functions including determine protein sub-cellular localisation via phosphoinositide interactions, while others bind protein partners. Other ligands include protein kinase C which is bound by the PH domain of AKAP13, serving to activate protein kinase D and mobilize a cardiac hypertrophy signaling pathway. 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 1207191405 480 LIHEGALLWKTAQGsRLKDVHVLLMTDVLVFMQEKDQKYVFPTLD-KPSVLCLQNLIVRDIANQQRGMFLISHSTP-PEM 557
Cdd:cd13392     1 LVRDGPVSLKNTAG-RLKEVQAVLLSDVLVFLQEKDQKYVFASLDqKSTVISLKKLIVREVAHEEKGLFLISMGIAdPEM 79

                          90       100
                  ....*....|....*....|..
gi 1207191405 558 YELHAASKDDRNTWMKIIQQTV 579
Cdd:cd13392    80 VEVHASSKEERNSWMQIIQDTI 101

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207191405 246 VIYELIQTEFNHVRTLRIMEGVFRRGMLEEVMMEMGVVHAIFPCLDQLLLIHTNFLsqllqrrsnsLASNSNRNFTIQKL 325
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL----------LEELLKEWISIQRI 70

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207191405 326 GDILVEQFSGQnaedmrKCYVEFCSRHLKAVKLYKELLARDKRFQQFIRRVSRGSLLRRHGVQECILLVTQRITKYPVLM 405
Cdd:pfam00621  71 GDIFLKFAPGF------KVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLL 144

                         170       180       190
                  ....*....|....*....|....*....|..
gi 1207191405 406 QRILDNTKGNEEESKSLAQSLTLIRELLCSVD 437
Cdd:pfam00621 145 KELLKHTPPDHPDYEDLKKALEAIKEVAKQIN 176

PDZ Rho guanine nucleotide exchange factor Pleckstrin homology (PH) domain; PRG (also called RhoGEF11) belongs to regulator of G-protein signaling (RGS) domain-containing RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. RhoGEFs activate Rho GTPases regulating cytoskeletal structure, gene transcription, and cell migration. PRG contains an N-terminal PDZ domain, a regulators of G-protein signaling-like (RGSL) domain, a linker region, and a C-terminal Dbl-homology (DH) and pleckstrin-homology (PH) domains which bind and catalyze the exchange of GDP for GTP on RhoA. As is the case in p115-RhoGEF, it is thought that the PRG activated by relieving autoinhibition caused by the linker region. 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 1207191405 470 FHGAELLRRGLIHEGALLWKTAQGSRLkDVHVLLMTDVLVFMQEKDQKYVFPTLDKPS------------VLCLQNLIVR 537
Cdd:cd13391    18 FKNLDLTTRRMIHEGPLTWRISKDKTL-DLHVLLLEDLLVLLQKQDEKLVLKCHSKTAvgssdskqtfspVLKLNSVLIR 96

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1207191405 538 DIANQQRGMFLISHST-PPEMYELHAASKDDRNTWMKIIQQTVSN 581
Cdd:cd13391    97 SVATDKRALFIICTSKlGPQIYELVALTSSEKNTWMELLEEAVRN 141

protein kinase C conserved region 1 (C1 domain) found in 190 kDa guanine nucleotide exchange factor (p190RhoGEF) and similar proteins; p190RhoGEF, also called Rho guanine nucleotide exchange factor (RGNEF), Rho guanine nucleotide exchange factor 28 (ARHGEF28), or RIP2, is a brain-enriched, RhoA-specific guanine nucleotide exchange factor that regulates signaling pathways downstream of integrins and growth factor receptors. It is involved in axonal branching, synapse formation and dendritic morphogenesis, as well as in focal adhesion formation, cell motility and B-lymphocytes activation. In addition to the Dbl homology (DH)-PH domain, p190RhoGEF contains an N-terminal C1 (Protein kinase C conserved region 1) domain. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1207191405  41 SRYSNGHLFTSLSVSATTLCSACNKSITAKEALSCPTCNVTIHNRCRDTLANCAKMKQ 98
Cdd:cd20876     2 EKQSNGHQFVTGSFSGPTLCVVCDKPVTGKELLQCSNCTVNVHKGCKESAPPCTKKLQ 59

Rho guanine nucleotide exchange factor Pleckstrin homology domain; p115RhoGEF (also called LSC, GEF1 or LBCL2) belongs to regulator of G-protein signaling (RGS) domain-containing RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. In addition to the Dbl homology (DH)-PH domain, p115RhoGEF contains an N-terminal RGS (Regulator of G-protein signalling) domain. The DH-PH domains bind and catalyze the exchange of GDP for GTP on RhoA. 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 1207191405 470 FHGAELLRRGLIHEGALLWKTAQGSRLkDVHVLLMTDVLVFMQEKDQKYVF--------PTLDKPSVLC----LQNLIVR 537
Cdd:cd14679     1 FKNIDITKKKLVHEGPLTWRVTKDKAI-EVHVLLLDDLLVLLQKQDERLVLkchsrtttPTPDGKQMLSpiikLNSAMTR 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1207191405 538 DIANQQRGMFLI-SHSTPPEMYELHAASKDDRNTWMKIIQQTV 579
Cdd:cd14679    80 EVATDRKAFYVIfTWEQGAQIYELVAQTVSERKNWCALISETA 122

protein kinase C conserved region 1 (C1 domain) found in uncharacterized Rho guanine nucleotide exchange factor 18 (ARHGEF18)-like proteins; The family includes a group of uncharacterized proteins that show high sequence similarity to vertebrate ARHGEF18, which is also called 114 kDa Rho-specific guanine nucleotide exchange factor (p114-Rho-GEF), p114RhoGEF, or septin-associated RhoGEF (SA-RhoGEF). ARHGEF18 acts as guanine nucleotide exchange factor (GEF) for RhoA GTPases. Its activation induces formation of actin stress fibers. ARHGEF18 also acts as a GEF for RAC1, inducing production of reactive oxygen species (ROS). Members of this family contain C1, RhoGEF or Dbl-homologous (DH), and Pleckstrin Homology (PH) domains, as well as a DUF5401 domain. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

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gi 1207191405  44 SNGHLFTSLSVSATTLCSACNKSITAKEALSCPTCNVTIHNRCRDTLANCA 94
Cdd:cd20879     1 VNGHQLVPGTFSSCATCSLCSKPLQNRNGLQCLNCAVNVHKNCKTLLTECS 51

protein kinase C conserved region 1 (C1 domain) superfamily; The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains. It contains the motif HX12CX2CXnCX2CX4HX2CX7C, where C and H are cysteine and histidine, respectively; X represents other residues; and n is either 13 or 14. C1 has a globular fold with two separate Zn(2+)-binding sites. It was originally discovered as lipid-binding modules in protein kinase C (PKC) isoforms. C1 domains that bind and respond to phorbol esters (PE) and diacylglycerol (DAG) are referred to as typical, and those that do not respond to PE and DAG are deemed atypical. A C1 domain may also be referred to as PKC or non-PKC C1, based on the parent protein's activity. Most C1 domain-containing non-PKC proteins act as lipid kinases and scaffolds, except PKD which acts as a protein kinase. PKC C1 domains play roles in membrane translocation and activation of the enzyme.

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gi 1207191405  47 HLFTSLSVSATTLCSACNKSIT--AKEALSCPTCNVTIHNRCRDTLA-NC 93
Cdd:cd00029     1 HRFVPTTFSSPTFCDVCGKLIWglFKQGLKCSDCGLVCHKKCLDKAPsPC 50

Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains); Some bind phorbol esters and diacylglycerol. Some bind RasGTP. Zinc-binding domains.

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gi 1207191405   47 HLFTSLSVSATTLCSACNKSI--TAKEALSCPTCNVTIHNRCRDTL-ANC 93
Cdd:smart00109   1 HKHVFRTFTKPTFCCVCRKSIwgSFKQGLRCSECKVKCHKKCADKVpKAC 50

protein kinase C conserved region 1 (C1 domain) found in the SH3 and cysteine-rich domain-containing protein (Stac) family; Stac proteins are putative adaptor proteins that are important for neuronal function. There are three mammalian members (Stac1, Stac2 and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. Stac proteins contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

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gi 1207191405  47 HLFTSLSVSATTLCSACNKSI--TAKEALSCPTCNVTIHNRCRDTLANCAK 95
Cdd:cd20817     1 HSFQEHTFKKPTFCDVCKELLvgLSKQGLRCKNCKMNVHHKCQEGVPDCSG 51

protein kinase C conserved region 1 (C1 domain) found in male germ cell RacGap (MgcRacGAP) and similar proteins; MgcRacGAP, also called Rac GTPase-activating protein 1 (RACGAP1) or protein CYK4, plays an important dual role in cytokinesis: i) it is part of centralspindlin-complex, together with the mitotic kinesin MKLP1, which is critical for the structure of the central spindle by promoting microtuble bundling; and ii) after phosphorylation by aurora B, MgcRacGAP becomes an effective regulator of RhoA and plays an important role in the assembly of the contractile ring and the initiation of cytokinesis. MgcRacGAP-like proteins contain an N-terminal C1 domain, and a C-terminal RhoGAP domain. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

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gi 1207191405  47 HLFTSLSVSATTLCSACNKSIT-AKEALSCPTCNVTIHNRCRDTL 90
Cdd:cd20821     3 HRFVSKTVIKPETCVVCGKRIKfGKKALKCKDCRVVCHPDCKDKL 47

protein kinase C conserved region 1 (C1 domain) found in SH3 and cysteine-rich domain-containing protein (Stac1) and similar proteins; Stac1, also called Src homology 3 and cysteine-rich domain-containing protein, promotes expression of the ion channel CACNA1H at the cell membrane, and thereby contributes to the regulation of channel activity. It plays a minor and redundant role in promoting the expression of calcium channel CACNA1S at the cell membrane, and thereby contributes to increased channel activity. It slows down the inactivation rate of the calcium channel CACNA1C. Stac1 contains a cysteine-rich C1 domain and two SH3 domains at the C-terminus. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

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gi 1207191405  46 GHLFTSLSVSATTLCSACNKSIT---AKEALSCPTCNVTIHNRCRDTLA 91
Cdd:cd20880     2 AHSFQEYIFKKPTFCDVCNHMIVgtnAKHGLRCKACKMSIHHKCTDGIG 50

protein kinase C conserved region 1 (C1 domain) found in Ras association domain-containing protein 5 (RASSF5) and similar proteins; RASSF5, also called new ras effector 1 (NORE1), or regulator for cell adhesion and polarization enriched in lymphoid tissues (RAPL), is a member of a family of RAS effectors, of which there are currently 8 members (RASSF1-8), all containing a Ras-association (RA) domain of the Ral-GDS/AF6 type. It is expressed as three transcripts (A-C) via differential promoter usage and alternative splicing. RASSF5A is a pro-apoptotic Ras effector and functions as a Ras regulated tumor suppressor. RASSF5C is regulated by Ras related protein and modulates cellular adhesion. RASSF5 is a potential tumor suppressor that seems to be involved in lymphocyte adhesion by linking RAP1A activation upon T-cell receptor or chemokine stimulation to integrin activation. It contains a C1 domain, which is descibed in this model. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

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gi 1207191405  46 GHLFTSLSVSATtLCSACNKSITAkEALSCPTCNVTIHNRCRD 88
Cdd:cd20886     3 GHRFEPGALGPG-WCDLCGRYILS-QALRCTNCKYTCHSECRD 43

first protein kinase C conserved region 1 (C1 domain) found in novel protein kinase C (nPKC) epsilon, eta, and similar proteins; PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domains. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. PKC-epsilon has been shown to behave as an oncoprotein. Its overexpression contributes to neoplastic transformation depending on the cell type. It contributes to oncogenesis by inducing disordered cell growth and inhibiting cell death. It also plays a role in tumor invasion and metastasis. PKC-epsilon has also been found to confer cardioprotection against ischemia and reperfusion-mediated damage. Other cellular functions include the regulation of gene expression, cell adhesion, and cell motility. PKC-eta is predominantly expressed in squamous epithelia, where it plays a crucial role in the signaling of cell-type specific differentiation. It is also expressed in pro-B cells and early-stage thymocytes, and acts as a key regulator in early B-cell development. PKC-eta increases glioblastoma multiforme (GBM) proliferation and resistance to radiation, and is being developed as a therapeutic target for the management of GBM. Members of this family contain two copies of the C1 domain. This model corresponds to the first one. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

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gi 1207191405  45 NGHLFTSLSVSATTLCSACNKSI---TAKEALSCPTCNVTIHNRC-RDTLANCAKMK 97
Cdd:cd20835     8 NGHKFMATYLRQPTYCSHCKDFIwgvIGKQGYQCQVCTCVVHKRChQLVVTKCPGNK 64

protein kinase C conserved region 1 (C1 domain) found in the Ras association domain-containing protein 1 (RASSF1)-like family; The RASSF1-like family includes RASSF1 and RASSF5. RASSF1 and RASSF5 are members of a family of RAS effectors, of which there are currently 8 members (RASSF1-8), all containing a Ras-association (RA) domain of the Ral-GDS/AF6 type. RASSF1 has eight transcripts (A-H) arising from alternative splicing and differential promoter usage. RASSF1A and 1C are the most extensively studied RASSF1; both are localized to microtubules and involved in the regulation of growth and migration. RASSF1 is a potential tumor suppressor that is required for death receptor-dependent apoptosis. RASSF5, also called new ras effector 1 (NORE1), or regulator for cell adhesion and polarization enriched in lymphoid tissues (RAPL), is expressed as three transcripts (A-C) via differential promoter usage and alternative splicing. RASSF5A is a pro-apoptotic Ras effector and functions as a Ras regulated tumor suppressor. RASSF5C is regulated by Ras related protein and modulates cellular adhesion. RASSF5 is a potential tumor suppressor that seems to be involved in lymphocyte adhesion by linking RAP1A activation upon T-cell receptor or chemokine stimulation to integrin activation. RASSF1 and RASSF5 contain a C1 domain, which is descibed in this model. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

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gi 1207191405  46 GHLFTSLSVSATTLCSACNKSI--TAKEALSCPTCNVTIHNRCRDTL 90
Cdd:cd20820     1 GHRFVPLELEQPTWCDLCGSVIlgLFRKCLRCANCKMTCHPRCRSLV 47

protein kinase C conserved region 1 (C1 domain) found in PDZ domain-containing protein 8 (PDZD8) and similar proteins; PDZD8, also called Sarcoma antigen NY-SAR-84/NY-SAR-104, is a molecular tethering protein that connects endoplasmic reticulum (ER) and mitochondrial membranes. PDZD8-dependent ER-mitochondria membrane tethering is essential for ER-mitochondria Ca2+ transfer. In neurons, it is involved in the regulation of dendritic Ca2+ dynamics by regulating mitochondrial Ca2+ uptake. PDZD8 also plays an indirect role in the regulation of cell morphology and cytoskeletal organization. It contains a PDZ domain and a C1 domain. This model describes the C1 domain, a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

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gi 1207191405  45 NGHLFTSLSVSATTLCSACNKSITAKEALSCPTCNVTIHNRCRD 88
Cdd:cd20825     2 GKHDFVLTQFQNATYCDFCKKKIWLKEAFQCRLCGMICHKKCLD 45