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 767924490  515 RMDKPQNMKHSGYLWAIGKNVWKRWKKRFFVLVQVSQYTFAMCSYREKKAEPQELLQLDGYTVDYTDPQP--GLEGGRAF 592
Cdd:cd01234     1 RMDKPQNMKHCGYLYALGKSVWKKWKKRYFVLVQVSQYTFAMCSYREKKSEPQEMMQLDGYTVDYTDPQPdlGLEGGRFF 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 767924490  593 FNAVKEGDTVIFASDDEQDRILWVQAMYRATGQSHKPVPPTQ 634
Cdd:cd01234    81 FNAVKEGDSVIFASDDENDRQLWVQALYRATGQSHKPVPPTQ 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 767924490  515 RMDKPQNMKHSGYLWAIGKNVWKRWKKRFFVLVQVSQYTFAMCSYREKKAEPQELLQLDGYTVDYTDPQP--GLEGGRAF 592
Cdd:cd01234     1 RMDKPQNMKHCGYLYALGKSVWKKWKKRYFVLVQVSQYTFAMCSYREKKSEPQEMMQLDGYTVDYTDPQPdlGLEGGRFF 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 767924490  593 FNAVKEGDTVIFASDDEQDRILWVQAMYRATGQSHKPVPPTQ 634
Cdd:cd01234    81 FNAVKEGDSVIFASDDENDRQLWVQALYRATGQSHKPVPPTQ 122

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767924490   523 KHSGYLWAIGKNVWKRWKKRFFVLVQVSQYTFAmCSYREKKAEPQELLQLDGYTVDYTDPQPglEGGRAF-----FNAVK 597
Cdd:pfam00169    2 VKEGWLLKKGGGKKKSWKKRYFVLFDGSLLYYK-DDKSGKSKEPKGSISLSGCEVVEVVASD--SPKRKFcfelrTGERT 78

                           90       100
                   ....*....|....*....|....*
gi 767924490   598 EGDTVIFASDDEQDRILWVQAMYRA 622
Cdd:pfam00169   79 GKRTYLLQAESEEERKDWIKAIQSA 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 767924490  515 RMDKPQNMKHSGYLWAIGKNVWKRWKKRFFVLVQVSQYTFAMCSYREKKAEPQELLQLDGYTVDYTDPQP--GLEGGRAF 592
Cdd:cd01234     1 RMDKPQNMKHCGYLYALGKSVWKKWKKRYFVLVQVSQYTFAMCSYREKKSEPQEMMQLDGYTVDYTDPQPdlGLEGGRFF 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 767924490  593 FNAVKEGDTVIFASDDEQDRILWVQAMYRATGQSHKPVPPTQ 634
Cdd:cd01234    81 FNAVKEGDSVIFASDDENDRQLWVQALYRATGQSHKPVPPTQ 122

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 767924490  525 SGYLWAIGKNVWKRWKKRFFVLVQvsqytfaMCSYREKKAEPQELL---QLDGYTVdyTDPQPGLEGGRAF-FNAVKEG- 599
Cdd:cd13248    10 SGWLHKQGGSGLKNWRKRWFVLKD-------NCLYYYKDPEEEKALgsiLLPSYTI--SPAPPSDEISRKFaFKAEHANm 80

                          90       100
                  ....*....|....*....|...
gi 767924490  600 DTVIFASDDEQDRILWVQAMYRA 622
Cdd:cd13248    81 RTYYFAADTAEEMEQWMNAMSLA 103

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 767924490  524 HSGYLWAIGKNVWKRWKKRFFVLvqvSQYTFAMCSYR-EKKAEPQELLQLDGyTVDYTDPQPGlEGGRAFFNAVKEGDTV 602
Cdd:cd00821     1 KEGYLLKRGGGGLKSWKKRWFVL---FEGVLLYYKSKkDSSYKPKGSIPLSG-ILEVEEVSPK-ERPHCFELVTPDGRTY 75

                          90
                  ....*....|....*..
gi 767924490  603 IFASDDEQDRILWVQAM 619
Cdd:cd00821    76 YLQADSEEERQEWLKAL 92

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 767924490  520 QNMKHSGYLWAIGKNVwKRWKKRFFVLVQVSQYTFAmcsyREKKAEPQELLQLDGYTVDYTDPQPGlEGGRAFFNAVKEG 599
Cdd:cd13263     1 ERPIKSGWLKKQGSIV-KNWQQRWFVLRGDQLYYYK----DEDDTKPQGTIPLPGNKVKEVPFNPE-EPGKFLFEIIPGG 74

                          90       100       110
                  ....*....|....*....|....*....|....
gi 767924490  600 ---------DTVIFASDDEQDRILWVQAMYRATG 624
Cdd:cd13263    75 ggdrmtsnhDSYLLMANSQAEMEEWVKVIRRVIG 108

Switch-associated protein-70 Pleckstrin homology (PH) domain; SWAP-70 (also called Differentially expressed in FDCP 6/DEF-6 or IRF4-binding protein) functions in cellular signal transduction pathways (in conjunction with Rac), regulates cell motility through actin rearrangement, and contributes to the transformation and invasion activity of mouse embryo fibroblasts. Metazoan SWAP-70 is found in B lymphocytes, mast cells, and in a variety of organs. Metazoan SWAP-70 contains an N-terminal EF-hand motif, a centrally located PH domain, and a C-terminal coiled-coil domain. The PH domain of Metazoan SWAP-70 contains a phosphoinositide-binding site and a nuclear localization signal (NLS), which localize SWAP-70 to the plasma membrane and nucleus, respectively. The NLS is a sequence of four Lys residues located at the N-terminus of the C-terminal a-helix; this is a unique characteristic of the Metazoan SWAP-70 PH domain. The SWAP-70 PH domain binds PtdIns(3,4,5)P3 and PtdIns(4,5)P2 embedded in lipid bilayer vesicles. There are additional plant SWAP70 proteins, but these are not included in this hierarchy. Rice SWAP70 (OsSWAP70) exhibits GEF activity toward the its Rho GTPase, OsRac1, and regulates chitin-induced production of reactive oxygen species and defense gene expression in rice. Arabidopsis SWAP70 (AtSWAP70) plays a role in both PAMP- and effector-triggered immunity. Plant SWAP70 contains both DH and PH domains, but their arrangement is the reverse of that in typical DH-PH-type Rho GEFs, wherein the DH domain is flanked by a C-terminal 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 767924490  526 GYLWAIGkNVWKRWKKRFFVL--VQVSQYTFAMCsyREKKAEpqelLQLDGYTVdyTDPQPGLEGGRAFFnAVKEGDTV- 602
Cdd:cd13273    12 GYLWKKG-HLLPTWTERWFVLkpNSLSYYKSEDL--KEKKGE----IALDSNCC--VESLPDREGKKCRF-LVKTPDKTy 81

                          90       100
                  ....*....|....*....|.
gi 767924490  603 -IFASDDEQdRILWVQAMYRA 622
Cdd:cd13273    82 eLSASDHKT-RQEWIAAIQTA 101