T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, N-terminal domain; Tiam1 activates Rac GTPases to induce membrane ruffling and cell motility while Tiam2 (also called STEF (SIF (still life) and Tiam1 like-exchange factor) contributes to neurite growth. Tiam1/2 are Dbl-family of GEFs that possess a Dbl(DH) domain with a PH domain in tandem. DH-PH domain catalyzes the GDP/GTP exchange reaction in the GTPase cycle and facillitating the switch between inactive GDP-bound and active GTP-bound states. Tiam1/2 possess two PH domains, which are often referred to as PHn and PHc domains. The DH-PH tandem domain is made up of the PHc domain while the PHn is part of a novel N-terminal PHCCEx domain which is made up of the PHn domain, a coiled coil region(CC), and an extra region (Ex). PHCCEx mediates binding to plasma membranes and signalling proteins in the activation of Rac GTPases. The PH domain resembles the beta-spectrin PH domain, suggesting non-canonical phosphatidylinositol binding. CC and Ex form a positively charged surface for protein binding. There are 2 motifs in Tiam1/2-interacting proteins that bind to the PHCCEx domain: Motif-I in CD44, ephrinBs, and the NMDA receptor and Motif-II in Par3 and JIP2.Neither of these fall in the PHn 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 568997998  503 GVVRKAGWLFFKPLVTLQKERKLELVARRKWKQYWVTLKGCTLLFYETYGKNSTEQNSAPRCALFAEDSIVQSVPEHPKK 582
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNKKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 568997998  583 EHVFCLSNSCGDVYLFQATSQTDLENWVTAIHSACASLFAKKHGKED 629
Cdd:cd01230    81 DFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACASAFARQHGKED 127

Raf-like Ras-binding domain;

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 568997998    832 QTYVHFQDNEGVTVTIKPEHRVEDVLALVCKMRQLEPTHYGLQLRKvVDKSVEWCVPALYEYMQEQVYDEI 902
Cdd:smart00455    1 TCKVHLPDNQRTVVKVRPGKTVRDALAKALKKRGLNPECCVVRLRG-EKKPLDLNQPISSLDGQELVVEEL 70

T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, N-terminal domain; Tiam1 activates Rac GTPases to induce membrane ruffling and cell motility while Tiam2 (also called STEF (SIF (still life) and Tiam1 like-exchange factor) contributes to neurite growth. Tiam1/2 are Dbl-family of GEFs that possess a Dbl(DH) domain with a PH domain in tandem. DH-PH domain catalyzes the GDP/GTP exchange reaction in the GTPase cycle and facillitating the switch between inactive GDP-bound and active GTP-bound states. Tiam1/2 possess two PH domains, which are often referred to as PHn and PHc domains. The DH-PH tandem domain is made up of the PHc domain while the PHn is part of a novel N-terminal PHCCEx domain which is made up of the PHn domain, a coiled coil region(CC), and an extra region (Ex). PHCCEx mediates binding to plasma membranes and signalling proteins in the activation of Rac GTPases. The PH domain resembles the beta-spectrin PH domain, suggesting non-canonical phosphatidylinositol binding. CC and Ex form a positively charged surface for protein binding. There are 2 motifs in Tiam1/2-interacting proteins that bind to the PHCCEx domain: Motif-I in CD44, ephrinBs, and the NMDA receptor and Motif-II in Par3 and JIP2.Neither of these fall in the PHn 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 568997998  503 GVVRKAGWLFFKPLVTLQKERKLELVARRKWKQYWVTLKGCTLLFYETYGKNSTEQNSAPRCALFAEDSIVQSVPEHPKK 582
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNKKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 568997998  583 EHVFCLSNSCGDVYLFQATSQTDLENWVTAIHSACASLFAKKHGKED 629
Cdd:cd01230    81 DFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACASAFARQHGKED 127

Raf-like Ras-binding domain;

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 568997998    832 QTYVHFQDNEGVTVTIKPEHRVEDVLALVCKMRQLEPTHYGLQLRKvVDKSVEWCVPALYEYMQEQVYDEI 902
Cdd:smart00455    1 TCKVHLPDNQRTVVKVRPGKTVRDALAKALKKRGLNPECCVVRLRG-EKKPLDLNQPISSLDGQELVVEEL 70

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997998   505 VRKAGWLFfkplvtlqkerKLELVARRKWKQYWVTLKGCTLLFYEtygKNSTEQNSAPRCALFAEDSIVQSV--PEHPKK 582
Cdd:pfam00169    1 VVKEGWLL-----------KKGGGKKKSWKKRYFVLFDGSLLYYK---DDKSGKSKEPKGSISLSGCEVVEVvaSDSPKR 66

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 568997998   583 EHVFCL---SNSCGDVYLFQATSQTDLENWVTAIHSACA 618
Cdd:pfam00169   67 KFCFELrtgERTGKRTYLLQAESEEERKDWIKAIQSAIR 105

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997998    909 VYDVQLTKTGDmtDFGFAVTVQVDEHQHlnrIFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLDIQQMEALFSEKSVG 988
Cdd:smart00228    2 PRLVELEKGGG--GLGFSLVGGKDEGGG---VVVSSVVPGSPAAKAGLRVGDVILEVNGTSVEGLTHLEAVDLLKKAGGK 76

                    ....*...
gi 568997998    989 LTL-VARP 995
Cdd:smart00228   77 VTLtVLRG 84

Periplasmic serine protease, S1-C subfamily, contain C-terminal PDZ domain [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 568997998  940 IFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLDiqQMEALFSEKSVGLTLvarPVTTRR 1000
Cdd:COG0265   203 VLVARVEPGSPAAKAGLRPGDVILAVDGKPVTSAR--DLQRLLASLKPGDTV---TLTVLR 258

serine endoprotease DegP;

                          10        20        30
                  ....*....|....*....|....*....|.
gi 568997998  941 FISDVLPDSLAYGGGLRKGNEITSLNGEPVS 971
Cdd:PRK10942  314 FVSQVLPNSSAAKAGIKAGDVITSLNGKPIS 344

T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, N-terminal domain; Tiam1 activates Rac GTPases to induce membrane ruffling and cell motility while Tiam2 (also called STEF (SIF (still life) and Tiam1 like-exchange factor) contributes to neurite growth. Tiam1/2 are Dbl-family of GEFs that possess a Dbl(DH) domain with a PH domain in tandem. DH-PH domain catalyzes the GDP/GTP exchange reaction in the GTPase cycle and facillitating the switch between inactive GDP-bound and active GTP-bound states. Tiam1/2 possess two PH domains, which are often referred to as PHn and PHc domains. The DH-PH tandem domain is made up of the PHc domain while the PHn is part of a novel N-terminal PHCCEx domain which is made up of the PHn domain, a coiled coil region(CC), and an extra region (Ex). PHCCEx mediates binding to plasma membranes and signalling proteins in the activation of Rac GTPases. The PH domain resembles the beta-spectrin PH domain, suggesting non-canonical phosphatidylinositol binding. CC and Ex form a positively charged surface for protein binding. There are 2 motifs in Tiam1/2-interacting proteins that bind to the PHCCEx domain: Motif-I in CD44, ephrinBs, and the NMDA receptor and Motif-II in Par3 and JIP2.Neither of these fall in the PHn 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 568997998  503 GVVRKAGWLFFKPLVTLQKERKLELVARRKWKQYWVTLKGCTLLFYETYGKNSTEQNSAPRCALFAEDSIVQSVPEHPKK 582
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNKKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 568997998  583 EHVFCLSNSCGDVYLFQATSQTDLENWVTAIHSACASLFAKKHGKED 629
Cdd:cd01230    81 DFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACASAFARQHGKED 127

Raf-like Ras-binding domain;

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 568997998    832 QTYVHFQDNEGVTVTIKPEHRVEDVLALVCKMRQLEPTHYGLQLRKvVDKSVEWCVPALYEYMQEQVYDEI 902
Cdd:smart00455    1 TCKVHLPDNQRTVVKVRPGKTVRDALAKALKKRGLNPECCVVRLRG-EKKPLDLNQPISSLDGQELVVEEL 70

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997998   505 VRKAGWLFfkplvtlqkerKLELVARRKWKQYWVTLKGCTLLFYEtygKNSTEQNSAPRCALFAEDSIVQSV--PEHPKK 582
Cdd:pfam00169    1 VVKEGWLL-----------KKGGGKKKSWKKRYFVLFDGSLLYYK---DDKSGKSKEPKGSISLSGCEVVEVvaSDSPKR 66

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 568997998   583 EHVFCL---SNSCGDVYLFQATSQTDLENWVTAIHSACA 618
Cdd:pfam00169   67 KFCFELrtgERTGKRTYLLQAESEEERKDWIKAIQSAIR 105

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 568997998  507 KAGWLFfkplvtlqkerKLELVARRKWKQYWVTLKGCTLLFYetygKNSTEQNSAPRCALFAEDSIVQSVPEHPKKEHVF 586
Cdd:cd00821     1 KEGYLL-----------KRGGGGLKSWKKRWFVLFEGVLLYY----KSKKDSSYKPKGSIPLSGILEVEEVSPKERPHCF 65

                          90       100
                  ....*....|....*....|....*..
gi 568997998  587 CLSNSCGDVYLFQATSQTDLENWVTAI 613
Cdd:cd00821    66 ELVTPDGRTYYLQADSEEERQEWLKAL 92

Beta-spectrin pleckstrin homology (PH) domain; Beta spectrin binds actin and functions as a major component of the cytoskeleton underlying cellular membranes. Beta spectrin consists of multiple spectrin repeats followed by a PH domain, which binds to inositol-1,4,5-trisphosphate. The PH domain of beta-spectrin is thought to play a role in the association of spectrin with the plasma membrane of cells. 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 568997998  522 ERKLEL------VARRKWKQYWVTLKGCTLLFY---ETYGKNSTEQNSAPRcalfaedSIVQSVPE----HPKKEHVFCL 588
Cdd:cd10571     6 ERKHEWesggkkASNRSWKNVYTVLRGQELSFYkdqKAAKSGITYAAEPPL-------NLYNAVCEvasdYTKKKHVFRL 78

                          90       100
                  ....*....|....*....|....*...
gi 568997998  589 SNSCGDVYLFQATSQTDLENWVTAIHSA 616
Cdd:cd10571    79 KLSDGAEFLFQAKDEEEMNQWVKKISFA 106

Pleckstrin homology domain; This Pleckstrin homology domain is found in some fungal species.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997998   530 RRKWKQYWVTLKGCTLLFYETYGKNSTEQ-------NSAPRCALFAEDSIVQSVPEHPKKEHVFCLSNSCGDVYLFQATS 602
Cdd:pfam15410   23 KRSWKMVYAVLKDLVLYLYKDEHPPESSQfedkkslKNAPVGKIRLHHALATPAPDYTKKSHVFRLQTADGAEYLFQTGS 102

                           90
                   ....*....|....*.
gi 568997998   603 QTDLENWVTAIHSACA 618
Cdd:pfam15410  103 PKELQEWVDTLNYWAA 118

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997998    909 VYDVQLTKTGDmtDFGFAVTVQVDEHQHlnrIFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLDIQQMEALFSEKSVG 988
Cdd:smart00228    2 PRLVELEKGGG--GLGFSLVGGKDEGGG---VVVSSVVPGSPAAKAGLRVGDVILEVNGTSVEGLTHLEAVDLLKKAGGK 76

                    ....*...
gi 568997998    989 LTL-VARP 995
Cdd:smart00228   77 VTLtVLRG 84

Rho GTPase activating protein 2 Pleckstrin homology (PH) domain; RhoGAP2 (also called RhoGap22 or ArhGap22) are involved in cell polarity, cell morphology and cytoskeletal organization. They activate a GTPase belonging to the RAS superfamily of small GTP-binding proteins. The encoded protein is insulin-responsive, is dependent on the kinase Akt, and requires the Akt-dependent 14-3-3 binding protein which binds sequentially to two serine residues resulting in regulation of cell motility. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) 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 568997998  503 GVVRKAGWLffkplvtlQKERKLelvaRRKWKQYWVTLKGCTLLFYETygknstEQNSAPRCALFAEDSIVQSVPEHPKK 582
Cdd:cd13378     1 EGVLKAGWL--------KKQRSI----MKNWQQRWFVLRGDQLFYYKD------EEETKPQGCISLQGSQVNELPPNPEE 62

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 568997998  583 --EHVFCLS-NSCGD---------VYLFQATSQTDLENWVTAI 613
Cdd:cd13378    63 pgKHLFEILpGGAGDrekvpmnheAFLLMANSQSDMEDWVKAI 105

Ral GEF with PH domain and SH3 binding motif 1 and 2 Pleckstrin homology (PH) domain; RalGPS1 (also called Ral GEF with PH domain and SH3 binding motif 1;RALGEF2/ Ral guanine nucleotide exchange factor 2; RalA exchange factor RalGPS1; Ral guanine nucleotide exchange factor RalGPS1A2; ras-specific guanine nucleotide-releasing factor RalGPS1) and RalGPS2 (also called Ral GEF with PH domain and SH3 binding motif 2; Ral-A exchange factor RalGPS2; ras-specific guanine nucleotide-releasing factor RalGPS22). They activate small GTPase Ral proteins such as RalA and RalB by stimulating the exchange of Ral bound GDP to GTP, thereby regulating various downstream cellular processes. Structurally they contain an N-terminal Cdc25-like catalytic domain, followed by a PXXP motif and a C-terminal PH domain. The Cdc25-like catalytic domain interacts with Ral and its PH domain ensures the correct membrane localization. Its PXXP motif is thought to interact with the SH3 domain of Grb2. 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 568997998  502 QGVVRKAgwlffkplvTLQKERKLELVARrkWKQYWVTLKGCTLLFYETYGKNSTEQN--SAPRCALFAEDSIVQSVPEH 579
Cdd:cd13310     3 QGCLRRK---------TVLKEGRKPTVSS--WQRYWVQLWGTSLVYYAPKSLKGTERSdfKSEPCKIVSISGWMVVLGDD 71

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 568997998  580 PKKEHVFCLSNS-CGDVYLFQATSQTDLENWVTAIHSACASL 620
Cdd:cd13310    72 PEHPDSFQLTDPeKGNVYKFRAGSRSNALLWLKHLKDACKGN 113

permuted PDZ domain of Deg/high-temperature requirement factor A (HtrA) family of housekeeping serine proteases and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of Deg/HtrA-type serine proteases that participate in folding and degradation of aberrant proteins, and in processing and maturation of native proteins. Typically, these proteases have an N-terminal serine protease domain and at least one C-terminal PDZ domain that recognizes substrates, and in some cases activates the protease function. An exception is yeast Nma11p which has two protease domains and four PDZ domains; its N-terminal half is comprised of a protease domain, followed by two PDZ domains, and its C-terminal half has a similar domain arrangement. HtrA-type proteases include the human HtrA1-4 and MBTPS2, tricorn protease, DegS, DegP and C-terminal processing peptidase, cyanobacterial serine proteases Hhoa, HhoB, and HtrA, and yeast Nma11p. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-termini of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains and as well as those with circular permutations and domain swapping of beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2); arranged as A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. This Deg/HtrA family PDZ domain is a circularly permuted PDZ domain which places beta-strand A at the C-terminus. Another permutation exists in the PDZ superfamily which places both beta-strands A and B on the C-terminus.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 568997998  927 VTVQVDEHQHLN-----RIFISDVLPDSLAYGGGLRKGNEITSLNGEPVSdlDIQQMEALFSEKSVGLTLVarpVTTRR 1000
Cdd:cd06779     9 ENISPLLAKELGlpvnrGVLVAEVIPGSPAAKAGLKEGDVILSVNGKPVT--SFNDLRAALDTKKPGDSLN---LTILR 82

Beta-spectrin pleckstrin homology (PH) domain; ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with RhoGAP domain. The ARHGAP members here all have a PH domain upstream of their C-terminal RhoGAP domain. Some have additional N-terminal SH3 and WW domains. The members here include: ARHGAP9, ARHGAP12, ARHGAP15, and ARHGAP27. ARHGAP27 and ARHGAP12 shared the common-domain structure, consisting of SH3, WW, PH, and RhoGAP domains. The PH domain of ArhGAP9 employs a non-canonical phosphoinositide binding mechanism, a variation of the spectrin- Ins(4,5)P2-binding mode, that gives rise to a unique PI binding profile, namely a preference for both PI(4,5)P2 and the PI 3-kinase products PI(3,4,5)P3 and PI(3,4)P2. This lipid binding mechanism is also employed by the PH domain of Tiam1 and Slm1. 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 568997998  530 RRKWKQYWVTLKGCTLLFYETygKNSTEQNSAPRCAlfAEDSI------VQSVPEHPKKEHVFCLSNSCGDVYLFQATSQ 603
Cdd:cd13233    19 RKNWSTSWVVLTSSHLLFYKD--AKSAAKSGNPYSK--PESSVdlrgasIEWAKEKSSRKNVFQISTVTGTEFLLQSDND 94

                          90
                  ....*....|...
gi 568997998  604 TDLENWVTAIHSA 616
Cdd:cd13233    95 TEIREWFDAIKAV 107

Autophagy-related protein 26/Sterol 3-beta-glucosyltransferase Pleckstrin homology (PH) domain, repeat 1; ATG26 (also called UGT51/UDP-glycosyltransferase 51), a member of the glycosyltransferase 28 family, resulting in the biosynthesis of sterol glucoside. ATG26 in decane metabolism and autophagy. There are 32 known autophagy-related (ATG) proteins, 17 are components of the core autophagic machinery essential for all autophagy-related pathways and 15 are the additional components required only for certain pathways or species. The core autophagic machinery includes 1) the ATG9 cycling system (ATG1, ATG2, ATG9, ATG13, ATG18, and ATG27), 2) the phosphatidylinositol 3-kinase complex (ATG6/VPS30, ATG14, VPS15, and ATG34), and 3) the ubiquitin-like protein system (ATG3, ATG4, ATG5, ATG7, ATG8, ATG10, ATG12, and ATG16). Less is known about how the core machinery is adapted or modulated with additional components to accommodate the nonselective sequestration of bulk cytosol (autophagosome formation) or selective sequestration of specific cargos (Cvt vesicle, pexophagosome, or bacteria-containing autophagosome formation). The pexophagosome-specific additions include the ATG30-ATG11-ATG17 receptor-adaptors complex, the coiled-coil protein ATG25, and the sterol glucosyltransferase ATG26. ATG26 is necessary for the degradation of medium peroxisomes. It contains 2 GRAM domains and a single PH domain. PH domains are only found in eukaryotes. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. PH domains also have diverse functions. They are often involved in targeting proteins to the plasma membrane, but 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 568997998  500 KEQGVVRKAGWLffkplvtlQKERKLelvaRRKWKQYWVTLKGCTLLFYEtygkNSTEqnsaprcALFAEDSI------- 572
Cdd:cd13215    16 KRSGAVIKSGYL--------SKRSKR----TLRYTRYWFVLKGDTLSWYN----SSTD-------LYFPAGTIdlryats 72

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 568997998  573 VQSVPEHPKKEHVFCLSNScGDVYLFQATSQTDLENWVTAI 613
Cdd:cd13215    73 IELSKSNGEATTSFKIVTN-SRTYKFKADSETSADEWVKAL 112

circularly permuted first PDZ domain (PDZ1) of Escherichia coli periplasmic serine endoprotease DegP and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of Escherichia coli DegP (also known as heat shock protein DegP and Protease Do) and related domains. DegP belongs to the HtrA family of housekeeping proteases. It acts as a protease, degrading transiently denatured and unfolded or misfolded proteins which accumulate in the periplasm following heat shock or other stress conditions, and as a molecular chaperone at low temperatures. DegP has two PDZ domains in addition to the protease domain; its PDZ1 domain is responsible for identifying the distinct substrate sequences that affect degradation (degron) of the substrate sequence, and its PDZ2 domain is responsible for combining with other DegP monomers to form a stable oligomer structure. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains and as well as those with circular permutations and domain swapping of beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2); arranged as A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. This DegP family PDZ domain 1 is a circularly permuted PDZ domain which places beta-strand A on the C-terminus. Another permutation exists in the PDZ superfamily which places both beta-strands A and B on the C-terminus.

                          10        20        30
                  ....*....|....*....|....*....|....
gi 568997998  940 IFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDL 973
Cdd:cd10839    27 ALVAQVLPDSPAAKAGLKAGDVILSLNGKPITSS 60

PDZ domain 2 of harmonin isoforms a, b, and c, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of harmonin isoforms a, b, and c, and related domains. Harmonin (also known as Usher Type 1C, PDZ-73 and AIE-75) is a key organizer of the Usher (USH) protein interactome. USH syndrome is the leading cause of hereditary sensory deaf-blindness in humans; three clinically distinct types of USH have been identified, type 1 to 3. The gene encoding harmonin (USH1C) is the causative gene for the USH type 1C phenotype. There are at least 10 alternatively spliced isoforms of harmonin, which are divided into three subclasses (a, b, and c). All isoforms contain the first two PDZ domains and the first coiled-coil domain. The a and b isoforms all have a third PDZ domain. The different PDZ domains are responsible for interactions with all known Usher syndrome type 1 proteins, and most Usher syndrome type 2 proteins. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This harmonin family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 568997998  940 IFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLDIQQ-MEALFSEKSvgLTLVAR 994
Cdd:cd06738    29 IFISNVKPGSLAEEVGLEVGDQIVEVNGTSFTNVDHKEaVMALKSSRH--LTITVR 82

circularly permuted second PDZ domain (PDZ2) of Escherichia coli periplasmic serine endoprotease DegP and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of Escherichia coli DegP (also known as heat shock protein DegP and Protease Do), and related domains. DegP belongs to the HtrA family of housekeeping proteases. It acts as a protease, degrading transiently denatured and unfolded or misfolded proteins which accumulate in the periplasm following heat shock or other stress conditions, and as a molecular chaperone at low temperatures. DegP has two PDZ domains in addition to the protease domain; its PDZ1 domain is responsible for the identifying the distinct substrate sequences that affect degradation (degron) of the substrate sequence, and its PDZ2 domain is responsible for the combining with other DegP monomers to form a stable oligomer structure. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains and as well as those with circular permutations and domain swapping of beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2); arranged as A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. This DegP family PDZ domain 2 is a circularly permuted PDZ domain which places beta-strand A on the C-terminus. Another permutation exists in the PDZ superfamily which places both beta-strands A and B on the C-terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 568997998  927 VTVQ-VDEHQHLNRIFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLD 974
Cdd:cd23084     6 ATVSnVTDEDGGKGVVVTEVDPGSPAAQSGLKKGDVIIGVNRQPVKSIA 54

Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain; CNK family members function as protein scaffolds, regulating the activity and the subcellular localization of RAS activated RAF. There is a single CNK protein present in Drosophila and Caenorhabditis elegans in contrast to mammals which have 3 CNK proteins (CNK1, CNK2, and CNK3). All of the CNK members contain a sterile a motif (SAM), a conserved region in CNK (CRIC) domain, and a PSD-95/DLG-1/ZO-1 (PDZ) domain, and a PH domain. A CNK2 splice variant CNK2A also has a PDZ domain-binding motif at its C terminus and Drosophila CNK (D-CNK) also has a domain known as the Raf-interacting region (RIR) that mediates binding of the Drosophila Raf kinase. This cd contains CNKs from insects, spiders, mollusks, and nematodes. 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 568997998  509 GWLFfkplvtlqkERKLELVARRKWKQYWVTLKGCTLlfyetYGKNSTEQNSApRCALFAEDSIVQSVPEHPKKEHVFCL 588
Cdd:cd13326     3 GWLY---------QRRRKGKGGGKWAKRWFVLKGSNL-----YGFRSQESTKA-DCVIFLPGFTVSPAPEVKSRKYAFKV 67

                          90       100
                  ....*....|....*....|....*
gi 568997998  589 SNScGDVYLFQATSQTDLENWVTAI 613
Cdd:cd13326    68 YHT-GTVFYFAAESQEDMKKWLDLL 91

PDZ domain of sorting nexin-27 (SNX27), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SNX27, and related domains. SNX27 is involved in retrograde transport from endosome to plasma membrane. The PDZ domain of SNX27 links cargo identification to retromer-mediated transport. SNX27 binds to the retromer complex (vacuolar protein sorting 26(VPS26)-VPS29-VPS35), via its PDZ domain binding to VPS26. The SNX27 PDZ domain also binds to cargo including the G-protein-coupled receptors (GPCRs): beta2-adrenergic receptor (beta2AR), beta1AR, parathyroid hormone receptor (PTHR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), NMDA receptors, 5-hydroxytryptamine 4a receptors, frizzled receptors, and somatostatin receptor subtype 5 (SSTR5). Additional binding partners of the SNX27 PDZ domain include G protein-gated inwardly rectifying potassium (Kir3) channels, angiotensin-converting enzyme 2 (ACE2), and PTEN (phosphatase and tensin homolog deleted on chromosome 10); PTEN binding to SNX27 prevents SNX27's association with the retromer complex. SNX27 has been reported to be a host factor needed for efficient entry of an engineered SARS-CoV-2 variant, the spike protein of which contains a deletion at the S1/S2 subunit cleavage site; the PDZ domain of SNX27 binds angiotensin-converting enzyme 2 (ACE2), and may be involved in recycling ACE2 to the plasma membrane, thereby promoting viral entry. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This SNX27-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997998  912 VQLTKTGdmTDFGFAVTVQVDEHQHLNRI---------FISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLDIQQMEALF 982
Cdd:cd23070     3 VTIVKSE--TGFGFNVRGQVSEGGQLRSIngelyaplqHVSAVLEGGAADKAGVRKGDRILEVNGVNVEGATHKQVVDLI 80

                          90
                  ....*....|..
gi 568997998  983 --SEKSVGLTLV 992
Cdd:cd23070    81 ksGGDELTLTVI 92

Tandem PH-domain-containing protein 2 Pleckstrin homology (PH) domain; The binding of TAPP2 (also called PLEKHA2) adaptors to PtdIns(3,4)P(2), but not PI(3,4, 5)P3, function as negative regulators of insulin and PI3K signalling pathways (i.e. TAPP/utrophin/syntrophin complex). TAPP2 contains two sequential PH domains in which the C-terminal PH domain specifically binds PtdIns(3,4)P2 with high affinity. The N-terminal PH domain does not interact with any phosphoinositide tested. They also contain a C-terminal PDZ-binding motif that interacts with several PDZ-binding proteins, including PTPN13 (known previously as PTPL1 or FAP-1) as well as the scaffolding proteins MUPP1 (multiple PDZ-domain-containing protein 1), syntrophin and utrophin. The members here are most sequence similar to TAPP2 proteins, but may not be actual TAPP2 proteins. 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 568997998  501 EQGVVRKAGWLffkplvtlqkERKLElvaRRK-WKQYWVTLKGCTLLFYetygKNSTEQnsapRCALFAEDSIVQSVPEH 579
Cdd:cd13255     2 ISEAVLKAGYL----------EKKGE---RRKtWKKRWFVLRPTKLAYY----KNDKEY----RLLRLIDLTDIHTCTEV 60

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 568997998  580 PKKEHVfclsNSCGDV-----YLFQATSQTDLENWVTAIHSACASL 620
Cdd:cd13255    61 QLKKHD----NTFGIVtpartFYVQADSKAEMESWISAINLARQAL 102

Rho GTPase activating protein 25 and related proteins Pleckstrin homology (PH) domain; RhoGAP25 (also called ArhGap25) like other RhoGaps are involved in cell polarity, cell morphology and cytoskeletal organization. They act as GTPase activators for the Rac-type GTPases by converting them to an inactive GDP-bound state and control actin remodeling by inactivating Rac downstream of Rho leading to suppress leading edge protrusion and promotes cell retraction to achieve cellular polarity and are able to suppress RAC1 and CDC42 activity in vitro. Overexpression of these proteins induces cell rounding with partial or complete disruption of actin stress fibers and formation of membrane ruffles, lamellipodia, and filopodia. This hierarchy contains RhoGAP22, RhoGAP24, and RhoGAP25. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) 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 568997998  507 KAGWLffkplvtlQKERKlelvARRKWKQYWVTLKGCTLLFYetygKNstEQNSAPRCALFAEDSIVQSVPEHPKKEHVF 586
Cdd:cd13263     5 KSGWL--------KKQGS----IVKNWQQRWFVLRGDQLYYY----KD--EDDTKPQGTIPLPGNKVKEVPFNPEEPGKF 66

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 568997998  587 CL----------SNSCGDVYLFQATSQTDLENWVTAI 613
Cdd:cd13263    67 LFeiipggggdrMTSNHDSYLLMANSQAEMEEWVKVI 103

C-terminal processing protease CtpA/Prc, contains a PDZ domain [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997998  924 GFAVTVQVDEhqhlNRIFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLDIQQMEALFSEK---SVGLTLVARPVTTRR 1000
Cdd:COG0793    61 GLGAELGEED----GKVVVVSVIPGSPAEKAGIKPGDIILAIDGKSVAGLTLDDAVKLLRGKagtKVTLTIKRPGEGEPI 136

                  ..
gi 568997998 1001 TL 1002
Cdd:COG0793   137 TV 138

PDZ domain of partitioning defective 6 (Par6), Drosophila Rho GTPase-activating protein 100F (RhoGAP100F), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of Par6 (also known as PAR6 or Par-6), RhoGAP100F, and related domains. Par6 is part of a conserved machinery that directs metazoan cell polarity, a process necessary for the function of diverse cell types. Par6 forms a cell polarity-regulatory complex with atypical protein kinase C (aPKC) and Par3. Par6 can also directly associate with PALS1 (proteins associated with Lin7, also known as Stardust) providing a link between the Par3/aPKC/Par6 complex and the PALS1-PATJ (protein-associated TJ) complex. Binding partners of the Par6-PDZ domain include Par3, PALS1/Stardust; leucine-rich repeat-containing protein netrin-G ligand-2 (NGL-2), human crumbs (CRB3) involve in the morphogenesis of the tight junctions in mammalian epithelial cells, and PAR-6 co-operates with the Par6 semi-CRIB domain to bind CDC42. CDC42 regulates the Par6 PDZ domain through an allosteric CRIB-PDZ transition. Drosophila RhoGAP100F, also known as synapse defective protein 1 homolog (syd-1 homolog), is a GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound form. The RhoGAP100F-PDZ domain binds the neurexin C terminus to control synapse formation at the Drosophila neuromuscular junction. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This Par6-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 568997998  940 IFISDVLPDSLAYGGG-LRKGNEITSLNGEPVSDLDIQQMEALFSEKSvGLTLVARP 995
Cdd:cd06718    29 IFISRLVLGSLADSTGlLAVGDEILEVNGVEVTGKSLDDVTDMMVAPT-RLIITVKP 84

Ras-specific guanine nucleotide-releasing factors 1 and 2 Pleckstrin homology (PH) domain; RasGRF1 (also called GRF1; CDC25Mm/Ras-specific nucleotide exchange factor CDC25; GNRP/Guanine nucleotide-releasing protein) and RasGRF2 (also called GRF2; Ras guanine nucleotide exchange factor 2) are a family of guanine nucleotide exchange factors (GEFs). They both promote the exchange of Ras-bound GDP by GTP, thereby regulating the RAS signaling pathway. RasGRF1 and RasGRF2 form homooligomers and heterooligomers. GRF1 has 3 isoforms and GRF2 has 2 isoforms. The longest isoforms of RasGRF1 and RasGRF2 contain the following domains: a Rho-GEF domain sandwiched between 2 PH domains, IQ domains, a REM (Ras exchanger motif) domain, and a Ras-GEF domainwhich gives them the capacity to activate both Ras and Rac GTPases in response to signals from a variety of neurotransmitter receptors. Their IQ domains allow them to act as calcium sensors to mediate the actions of NMDA-type and calcium-permeable AMPA-type glutamate receptors. GRF1 also mediates the action of dopamine receptors that signal through cAMP. GRF1 and GRF2 play strikingly different roles in regulating MAP kinase family members, neuronal synaptic plasticity, specific forms of learning and memory, and behavioral responses to psychoactive drugs. 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 568997998  532 KWKQYWVTLKGCTLLFYETygknstEQNSAPRCALFAEDSIVQSVP---------EHPKKEHVFCLS--NSCGDVYLFQA 600
Cdd:cd13261    20 KWHERWFALYQNLLFYFEN------ESSSRPSGLYLLEGCYCERLPtpkgalkgkDHLEKQHYFTISfrHENQRQYELRA 93

                          90
                  ....*....|....*.
gi 568997998  601 TSQTDLENWVTAIHSA 616
Cdd:cd13261    94 ETESDCDEWVEAIKQA 109

PDZ domain of Drosophila melanogaster PDZ and LIM domain protein Zasp52 (also known as Zasp), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of Drosophila melanogaster Zasp52 and related domains. Drosophila melanogaster Zasp52 (also known as Z band alternatively spliced PDZ-motif protein or Zasp) colocalizes with integrins at myotendinous junctions and with alpha-actinin at Z-disks and is required for muscle attachment as well as Z-disk assembly and maintenance. The Zasp52 actin-binding site includes the extended PDZ domain and the ZM region. The Zasp52-PDZ domain is required for myofibril assembly. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This Zasp52-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 568997998  911 DVQLTKTGDMTDFGFAVTVQVDEHQHLnriFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLDIQQMEALF 982
Cdd:cd23068     1 NIRLRRDDSNTPWGFRLQGGADFGQPL---SIQKVNPGSPADKAGLRRGDVILRINGTDTSNLTHKQAQDLI 69

FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 2; 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 second 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 568997998  533 WKQYWVTLKGCTLLFYETYgknsteQNSAPRCALFAEDSIVQ--SVPEHPKKEHVFCLSNScGDVYLFQATSQTDLENWV 610
Cdd:cd13235    19 WQKLWVVFTNFCLFFYKSH------QDEFPLASLPLLGYSVGlpSEADNIDKDYVFKLQFK-SHVYFFRAESEYTFERWM 91

                  ....*.
gi 568997998  611 TAIHSA 616
Cdd:cd13235    92 EVIRSA 97

circularly permuted PDZ domain of C-terminal processing peptidase (CPP), a serine protease, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of CPP (also known as tail-specific protease, PRC protein, Protease Re, and Photosystem II D1 protein processing peptidase), and related domains. CPP belongs to the peptidase S41A family. It cleaves a C-terminal 11 residue peptide from the precursor form of penicillin-binding protein 3, and may have a role in protecting bacterium from thermal and osmotic stresses. In the plant chloroplast, the enzyme removes the C-terminal extension of the D1 polypeptide of photosystem II. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains and as well as those with circular permutations and domain swapping of beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2); arranged as A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. This CPP-like PDZ domain is a circularly permuted PDZ domain which places beta-strand A on the C-terminus. Another permutation exists in the PDZ superfamily which places both beta-strands A and B on the C-terminus.

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gi 568997998  927 VTVQVDEHqhlNRIFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLDIQQ 977
Cdd:cd06782     6 IEIGKDDD---GYLVVVSPIPGGPAEKAGIKPGDVIVAVDGESVRGMSLDE 53

serine endoprotease DegP;

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gi 568997998  941 FISDVLPDSLAYGGGLRKGNEITSLNGEPVS 971
Cdd:PRK10942  314 FVSQVLPNSSAAKAGIKAGDVITSLNGKPIS 344