Ca2+-dependent activator protein (also called CAPS) Pleckstrin homology (PH) domain; CADPS/CAPS consists of two members, CAPS1 which regulates catecholamine release from neuroendocrine cells and CAPS2 which is involved in the release of two neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) from cerebellar granule cells. CADPS plays an important role in vesicle exocytosis in neurons and endocrine cells where it functions to prime the exocytic machinery for Ca2+-triggered fusion. Priming involves the assembly of trans SNARE complexes. The initial interaction of vesicles with target membranes is mediated by diverse stage-specific tethering factors or multi-subunit tethering complexes. CADPS and Munc13 proteins are proposed to be the functional homologs of the stage-specific tethering factors that prime membrane fusion. Interestingly, regions in the C-terminal half of CADPS are similar to the C-terminal region of Munc13-1 that was reported to bind syntaxin-1. CADPS has independent interactions with each of the SNARE proteins (Q-SNARE and R-SNARE) required for vesicle fusion. CADPS interacts with Q-SNARE proteins syntaxin-1 (H3 SNARE) and SNAP-25 (SN1) and might promote Q-SNARE heterodimer formation. Through its N-terminal R-SNARE VAMP-2 interactions, CADPS bound to heterodimeric Q-SNARE complexes could be involved in catalyzing the zippering of VAMP-2 into recipient complexes. It also contains a central PH domain that binds to phosphoinositide 4,5 bisphosphate containing liposomes. Membrane association may also be mediated by binding to phosphatidlyserine via general electrostatic interactions. 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 78706458  565 RLDKPLNMKHCGYLYAIGKSVWKKWKRRYFVLVQVSQYTFAMCSYKEKKSEPSEMMQLDGYTVDYIEAASAnlmfgIDLN 644
Cdd:cd01234    1 RMDKPQNMKHCGYLYALGKSVWKKWKKRYFVLVQVSQYTFAMCSYREKKSEPQEMMQLDGYTVDYTDPQPD-----LGLE 75

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 78706458  645 GGRYFFNAVREGDSISFACDDENECSLWVMAMYRATGQSHKPTPPIT 691
Cdd:cd01234   76 GGRFFFNAVKEGDSVIFASDDENDRQLWVQALYRATGQSHKPVPPTQ 122

Ca2+-dependent activator protein (also called CAPS) Pleckstrin homology (PH) domain; CADPS/CAPS consists of two members, CAPS1 which regulates catecholamine release from neuroendocrine cells and CAPS2 which is involved in the release of two neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) from cerebellar granule cells. CADPS plays an important role in vesicle exocytosis in neurons and endocrine cells where it functions to prime the exocytic machinery for Ca2+-triggered fusion. Priming involves the assembly of trans SNARE complexes. The initial interaction of vesicles with target membranes is mediated by diverse stage-specific tethering factors or multi-subunit tethering complexes. CADPS and Munc13 proteins are proposed to be the functional homologs of the stage-specific tethering factors that prime membrane fusion. Interestingly, regions in the C-terminal half of CADPS are similar to the C-terminal region of Munc13-1 that was reported to bind syntaxin-1. CADPS has independent interactions with each of the SNARE proteins (Q-SNARE and R-SNARE) required for vesicle fusion. CADPS interacts with Q-SNARE proteins syntaxin-1 (H3 SNARE) and SNAP-25 (SN1) and might promote Q-SNARE heterodimer formation. Through its N-terminal R-SNARE VAMP-2 interactions, CADPS bound to heterodimeric Q-SNARE complexes could be involved in catalyzing the zippering of VAMP-2 into recipient complexes. It also contains a central PH domain that binds to phosphoinositide 4,5 bisphosphate containing liposomes. Membrane association may also be mediated by binding to phosphatidlyserine via general electrostatic interactions. 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 78706458  565 RLDKPLNMKHCGYLYAIGKSVWKKWKRRYFVLVQVSQYTFAMCSYKEKKSEPSEMMQLDGYTVDYIEAASAnlmfgIDLN 644
Cdd:cd01234    1 RMDKPQNMKHCGYLYALGKSVWKKWKKRYFVLVQVSQYTFAMCSYREKKSEPQEMMQLDGYTVDYTDPQPD-----LGLE 75

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 78706458  645 GGRYFFNAVREGDSISFACDDENECSLWVMAMYRATGQSHKPTPPIT 691
Cdd:cd01234   76 GGRFFFNAVKEGDSVIFASDDENDRQLWVQALYRATGQSHKPVPPTQ 122

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 78706458    573 KHCGYLYAIGKSVWKKWKRRYFVLvqvSQYTFAMCSYK--EKKSEPSEMMQLDGYTVDYIEAAS---ANLMFGIdlnggr 647
Cdd:pfam00169    2 VKEGWLLKKGGGKKKSWKKRYFVL---FDGSLLYYKDDksGKSKEPKGSISLSGCEVVEVVASDspkRKFCFEL------ 72

                           90       100       110
                   ....*....|....*....|....*....|..
gi 78706458    648 yFFNAVREGDSISFACDDENECSLWVMAMYRA 679
Cdd:pfam00169   73 -RTGERTGKRTYLLQAESEEERKDWIKAIQSA 103

Ca2+-dependent activator protein (also called CAPS) Pleckstrin homology (PH) domain; CADPS/CAPS consists of two members, CAPS1 which regulates catecholamine release from neuroendocrine cells and CAPS2 which is involved in the release of two neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) from cerebellar granule cells. CADPS plays an important role in vesicle exocytosis in neurons and endocrine cells where it functions to prime the exocytic machinery for Ca2+-triggered fusion. Priming involves the assembly of trans SNARE complexes. The initial interaction of vesicles with target membranes is mediated by diverse stage-specific tethering factors or multi-subunit tethering complexes. CADPS and Munc13 proteins are proposed to be the functional homologs of the stage-specific tethering factors that prime membrane fusion. Interestingly, regions in the C-terminal half of CADPS are similar to the C-terminal region of Munc13-1 that was reported to bind syntaxin-1. CADPS has independent interactions with each of the SNARE proteins (Q-SNARE and R-SNARE) required for vesicle fusion. CADPS interacts with Q-SNARE proteins syntaxin-1 (H3 SNARE) and SNAP-25 (SN1) and might promote Q-SNARE heterodimer formation. Through its N-terminal R-SNARE VAMP-2 interactions, CADPS bound to heterodimeric Q-SNARE complexes could be involved in catalyzing the zippering of VAMP-2 into recipient complexes. It also contains a central PH domain that binds to phosphoinositide 4,5 bisphosphate containing liposomes. Membrane association may also be mediated by binding to phosphatidlyserine via general electrostatic interactions. 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 78706458  565 RLDKPLNMKHCGYLYAIGKSVWKKWKRRYFVLVQVSQYTFAMCSYKEKKSEPSEMMQLDGYTVDYIEAASAnlmfgIDLN 644
Cdd:cd01234    1 RMDKPQNMKHCGYLYALGKSVWKKWKKRYFVLVQVSQYTFAMCSYREKKSEPQEMMQLDGYTVDYTDPQPD-----LGLE 75

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 78706458  645 GGRYFFNAVREGDSISFACDDENECSLWVMAMYRATGQSHKPTPPIT 691
Cdd:cd01234   76 GGRFFFNAVKEGDSVIFASDDENDRQLWVQALYRATGQSHKPVPPTQ 122

SH3 domain-binding protein 2 Pleckstrin homology (PH) domain; SH3BP2 (the gene that encodes the adaptor protein 3BP2), HD, ITU, IT10C3, and ADD1 are located near the Huntington's Disease Gene on Human Chromosome 4pl6.3. SH3BP2 lies in a region that is often missing in individuals with Wolf-Hirschhorn syndrome (WHS). Gain of function mutations in SH3BP2 causes enhanced B-cell antigen receptor (BCR)-mediated activation of nuclear factor of activated T cells (NFAT), resulting in a rare, genetic disorder called cherubism. This results in an increase in the signaling complex formation with Syk, phospholipase C-gamma2 (PLC-gamma2), and Vav1. It was recently discovered that Tankyrase regulates 3BP2 stability through ADP-ribosylation and ubiquitylation by the E3-ubiquitin ligase. Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the Src, Syk, and Vav signaling pathways. SH3BP2 is also a potential negative regulator of the abl oncogene. 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 78706458  574 HCGYLYAIGKS--VWKKWKRRYFVLVQVSQYTFAmcSYKEKKsePSEMMQLDGYTVDYIEAASANLMFGIDL----NGGR 647
Cdd:cd13308   11 HSGTLTKKGGSqkTLQNWQLRYVIIHQGCVYYYK--NDQSAK--PKGVFSLNGYNRRAAEERTSKLKFVFKIihlsPDHR 86

                         90       100       110
                 ....*....|....*....|....*....|.
gi 78706458  648 YFFnavregdsisFACDDENECSLWvMAMYR 678
Cdd:cd13308   87 TWY----------FAAKSEDEMSEW-MEYIR 106

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 78706458  574 HCGYLYAIGKSVWKKWKRRYFVLvqvSQYTFAMCSYK-EKKSEPSEMMQLDG-YTVDYIEAASANLMFGIDLNGGRyffn 651
Cdd:cd00821    1 KEGYLLKRGGGGLKSWKKRWFVL---FEGVLLYYKSKkDSSYKPKGSIPLSGiLEVEEVSPKERPHCFELVTPDGR---- 73

                         90       100
                 ....*....|....*....|....*
gi 78706458  652 avregdSISFACDDENECSLWVMAM 676
Cdd:cd00821   74 ------TYYLQADSEEERQEWLKAL 92

Phosphoinositol 3-phosphate binding proteins 1, 2, and 3 pleckstrin homology (PH) domain; PEPP1 (also called PLEKHA4/PH domain-containing family A member 4 and RHOXF1/Rhox homeobox family member 1), and related homologs PEPP2 (also called PLEKHA5/PH domain-containing family A member 5) and PEPP3 (also called PLEKHA6/PH domain-containing family A member 6), have PH domains that interact specifically with PtdIns(3,4)P3. Other proteins that bind PtdIns(3,4)P3 specifically are: TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns3P AtPH1, and Ptd- Ins(3,5)P2 (centaurin-beta2). All of these proteins contain at least 5 of the 6 conserved amino acids that make up the putative phosphatidylinositol 3,4,5- trisphosphate-binding motif (PPBM) located at their N-terminus. 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 78706458  576 GYLYAIGKSVWKKWKRRYFVLVQvsqytFAMCSYK-EKKSEPSEMMQLDGYTvdyIEAASANlmfgiDLNGGRYFFNAVR 654
Cdd:cd13248   11 GWLHKQGGSGLKNWRKRWFVLKD-----NCLYYYKdPEEEKALGSILLPSYT---ISPAPPS-----DEISRKFAFKAEH 77

                         90       100
                 ....*....|....*....|....*.
gi 78706458  655 EG-DSISFACDDENECSLWVMAMYRA 679
Cdd:cd13248   78 ANmRTYYFAADTAEEMEQWMNAMSLA 103