chromosomal replication initiator protein DnaA;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679  261 AGPEPASEPGSPYPEGPRVPGGGEQPaqpngwqyhSPSRPGSTAFPSQDGETGGHRRSFPPRTNPDKIAQRKS----SMN 336
Cdd:PRK14086   92 AGEPAPPPPHARRTSEPELPRPGRRP---------YEGYGGPRADDRPPGLPRQDQLPTARPAYPAYQQRPEPgawpRAA 162

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679  337 QLQQWVNLRRGVPPPEDLRSPSRFYPVSRRVPEyygPYSSQYPDDYQYYPPGVRPESICSMPAYDRISPPWALEDKRHAF 416
Cdd:PRK14086  163 DDYGWQQQRLGFPPRAPYASPASYAPEQERDRE---PYDAGRPEYDQRRRDYDHPRPDWDRPRRDRTDRPEPPPGAGHVH 239

                         170       180
                  ....*....|....*....|
gi 578800679  417 RNGGGPAYQLREWKEPASYG 436
Cdd:PRK14086  240 RGGPGPPERDDAPVVPIRPS 259

Uncharacterized conserved protein YhaN, contains AAA domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679  564 QLQRNLEYLDQQMSESETLISMVNRMVENsspRSQLFMQVPPYPEVfrdslhtyklneQDTDKLLGKLCEQNKVVREQDR 643
Cdd:COG4717    92 ELQEELEELEEELEELEAELEELREELEK---LEKLLQLLPLYQEL------------EALEAELAELPERLEELEERLE 156

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679  644 LVQQLRAEKESLESALMGTHQELEmfgsqpaypEKLRHKKDSLQNQLINIRVELSQATTALTNSTIEYEHLESEVSALHD 723
Cdd:COG4717   157 ELRELEEELEELEAELAELQEELE---------ELLEQLSLATEEELQDLAEELEELQQRLAELEEELEEAQEELEELEE 227

                         170       180
                  ....*....|....*....|....*.
gi 578800679  724 DLwEQLNLDTQNEVLNRQIQKEIWRI 749
Cdd:COG4717   228 EL-EQLENELEAAALEERLKEARLLL 252

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679     60 VTKAGWLFKQASSGVKQWNKRWFVLVDRCLFYYKDEKEESIL---GSIPLLSFRVAAVQPSDNISRKHTFKVTvcwvdea 136
Cdd:smart00233    1 VIKEGWLYKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYkpkGSIDLSGCTVREAPDPDSSKKPHCFEIK------- 73

                            90       100       110       120
                    ....*....|....*....|....*....|....*....|..
gi 578800679    137 easstrclspqaeHAGVRTYFFSAESPEEQEAWIQAMGEAAR 178
Cdd:smart00233   74 -------------TSDRKTLLLQAESEEEREKWVEALRKAIA 102

chromosomal replication initiator protein DnaA;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679  261 AGPEPASEPGSPYPEGPRVPGGGEQPaqpngwqyhSPSRPGSTAFPSQDGETGGHRRSFPPRTNPDKIAQRKS----SMN 336
Cdd:PRK14086   92 AGEPAPPPPHARRTSEPELPRPGRRP---------YEGYGGPRADDRPPGLPRQDQLPTARPAYPAYQQRPEPgawpRAA 162

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679  337 QLQQWVNLRRGVPPPEDLRSPSRFYPVSRRVPEyygPYSSQYPDDYQYYPPGVRPESICSMPAYDRISPPWALEDKRHAF 416
Cdd:PRK14086  163 DDYGWQQQRLGFPPRAPYASPASYAPEQERDRE---PYDAGRPEYDQRRRDYDHPRPDWDRPRRDRTDRPEPPPGAGHVH 239

                         170       180
                  ....*....|....*....|
gi 578800679  417 RNGGGPAYQLREWKEPASYG 436
Cdd:PRK14086  240 RGGPGPPERDDAPVVPIRPS 259

Uncharacterized conserved protein YhaN, contains AAA domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679  564 QLQRNLEYLDQQMSESETLISMVNRMVENsspRSQLFMQVPPYPEVfrdslhtyklneQDTDKLLGKLCEQNKVVREQDR 643
Cdd:COG4717    92 ELQEELEELEEELEELEAELEELREELEK---LEKLLQLLPLYQEL------------EALEAELAELPERLEELEERLE 156

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679  644 LVQQLRAEKESLESALMGTHQELEmfgsqpaypEKLRHKKDSLQNQLINIRVELSQATTALTNSTIEYEHLESEVSALHD 723
Cdd:COG4717   157 ELRELEEELEELEAELAELQEELE---------ELLEQLSLATEEELQDLAEELEELQQRLAELEEELEEAQEELEELEE 227

                         170       180
                  ....*....|....*....|....*.
gi 578800679  724 DLwEQLNLDTQNEVLNRQIQKEIWRI 749
Cdd:COG4717   228 EL-EQLENELEAAALEERLKEARLLL 252

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679     60 VTKAGWLFKQASSGVKQWNKRWFVLVDRCLFYYKDEKEESIL---GSIPLLSFRVAAVQPSDNISRKHTFKVTvcwvdea 136
Cdd:smart00233    1 VIKEGWLYKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYkpkGSIDLSGCTVREAPDPDSSKKPHCFEIK------- 73

                            90       100       110       120
                    ....*....|....*....|....*....|....*....|..
gi 578800679    137 easstrclspqaeHAGVRTYFFSAESPEEQEAWIQAMGEAAR 178
Cdd:smart00233   74 -------------TSDRKTLLLQAESEEEREKWVEALRKAIA 102

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 578800679   62 KAGWLFKQASSGVKQWNKRWFVLVDRCLFYYKDEKEES--ILGSIPLLSfrVAAVQPSDNISRKHTFKVTvcwvdeaeas 139
Cdd:cd00821     1 KEGYLLKRGGGGLKSWKKRWFVLFEGVLLYYKSKKDSSykPKGSIPLSG--ILEVEEVSPKERPHCFELV---------- 68

                          90       100       110
                  ....*....|....*....|....*....|....
gi 578800679  140 strclspqaeHAGVRTYFFSAESPEEQEAWIQAM 173
Cdd:cd00821    69 ----------TPDGRTYYLQADSEEERQEWLKAL 92

ArfGAP with coiled-coil, ankyrin repeat and PH domains Pleckstrin homology (PH) domain; ACAP (also called centaurin beta) functions both as a Rab35 effector and as an Arf6-GTPase-activating protein (GAP) by which it controls actin remodeling and membrane trafficking. ACAP contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain, a phospholipid-binding domain, a PH domain, a GAP domain, and four ankyrin repeats. The AZAPs constitute a family of Arf GAPs that are characterized by an NH2-terminal pleckstrin homology (PH) domain and a central Arf GAP domain followed by two or more ankyrin repeats. On the basis of sequence and domain organization, the AZAP family is further subdivided into four subfamilies: 1) the ACAPs contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain (a phospholipid-binding domain that is thought to sense membrane curvature), a single PH domain followed by the GAP domain, and four ankyrin repeats; 2) the ASAPs also contain an NH2-terminal BAR domain, the tandem PH domain/GAP domain, three ankyrin repeats, two proline-rich regions, and a COOH-terminal Src homology 3 domain; 3) the AGAPs contain an NH2-terminal GTPase-like domain (GLD), a split PH domain, and the GAP domain followed by four ankyrin repeats; and 4) the ARAPs contain both an Arf GAP domain and a Rho GAP domain, as well as an NH2-terminal sterile-a motif (SAM), a proline-rich region, a GTPase-binding domain, and five PH domains. PMID 18003747 and 19055940 Centaurin can bind to phosphatidlyinositol (3,4,5)P3. 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 578800679   62 KAGWLFKQASSGVKQWNKRWFVLVDRCLFYYKDEKEESIlgSIPLLSFRVAAVQPSDNISRKHTFKVtvcwvdeaeasst 141
Cdd:cd13250     1 KEGYLFKRSSNAFKTWKRRWFSLQNGQLYYQKRDKKDEP--TVMVEDLRLCTVKPTEDSDRRFCFEV------------- 65

                          90       100       110
                  ....*....|....*....|....*....|..
gi 578800679  142 rcLSPQaehagvRTYFFSAESPEEQEAWIQAM 173
Cdd:cd13250    66 --ISPT------KSYMLQAESEEDRQAWIQAI 89

Fungal proteins Pleckstrin homology (PH) domain, repeat 1; The functions of these fungal proteins are unknown, but they all contain 2 PH domains. This cd represents the first PH repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578800679   60 VTKAGWLFKQaSSGVKQWNKRWFVLVDRCLFYYKDEKEESILGSIPLLSfrVAAVQPSDNISRKHTFKVtvcwvdeaeas 139
Cdd:cd13298     6 VLKSGYLLKR-SRKTKNWKKRWVVLRPCQLSYYKDEKEYKLRRVINLSE--LLAVAPLKDKKRKNVFGI----------- 71

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 578800679  140 strcLSPQaehagvRTYFFSAESPEEQEAWIQAMGEAAR 178
Cdd:cd13298    72 ----YTPS------KNLHFRATSEKDANEWVEALREEFR 100

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. 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 578800679   62 KAGWLFKqASSGVKQWNKRWFVLVDRCLFYYKDEKEES--ILGSIPLLSFrvAAVQPSDnisRKHTFKVTvcwvdeaeas 139
Cdd:cd13282     1 KAGYLTK-LGGKVKTWKRRWFVLKNGELFYYKSPNDVIrkPQGQIALDGS--CEIARAE---GAQTFEIV---------- 64

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 578800679  140 strclspqAEHagvRTYFFSAESPEEQEAWIQAMGEAARVQ 180
Cdd:cd13282    65 --------TEK---RTYYLTADSENDLDEWIRVIQNVLRRQ 94

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 578800679   60 VTKAGWLFKQASS--GVKQWNKRWFVLVDRCLFYYKDEKEESILGSIPLLSFRVAAvQPSDNISRKHTFKVTvcwvdeae 137
Cdd:cd13308     9 VIHSGTLTKKGGSqkTLQNWQLRYVIIHQGCVYYYKNDQSAKPKGVFSLNGYNRRA-AEERTSKLKFVFKII-------- 79

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 578800679  138 asstrclSPQAEHagvRTYFFSAESPEEQEAWIQAMGEA 176
Cdd:cd13308    80 -------HLSPDH---RTWYFAAKSEDEMSEWMEYIRRE 108

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 578800679   60 VTKAGWLFKQASSGvKQWNKRWFVLVDRCLFYYKDEKEESILGSIPLLSfrVAAVQPSDNISRKHTFKVtvcwvdeaeas 139
Cdd:cd13255     6 VLKAGYLEKKGERR-KTWKKRWFVLRPTKLAYYKNDKEYRLLRLIDLTD--IHTCTEVQLKKHDNTFGI----------- 71

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 578800679  140 strcLSPQaehagvRTYFFSAESPEEQEAWIQAMGEA 176
Cdd:cd13255    72 ----VTPA------RTFYVQADSKAEMESWISAINLA 98

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 578800679   63 AGWL---FKQaSSGvkqWNKRWFVLVDRCLFYYKDEKEESILGSIPLLSFRVAAVQPSDNISRKHTFKVtvcwvdeaeas 139
Cdd:cd13235     6 SGYLlrkFKN-SNG---WQKLWVVFTNFCLFFYKSHQDEFPLASLPLLGYSVGLPSEADNIDKDYVFKL----------- 70

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 578800679  140 strclspqaeHAGVRTYFFSAESPEEQEAWIQAMGEAA 177
Cdd:cd13235    71 ----------QFKSHVYFFRAESEYTFERWMEVIRSAT 98

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, with the exception of CNK3, 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 mammals, chickens, amphibians, fish, and crustacea. 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 578800679   64 GWLFKQASSG---VKQWNKRWFVLVDRCLFYYKDEKEESILGSIPLLSFRVAAVQPSdniSRKHTFKVTvcwvdeaeass 140
Cdd:cd01260    17 GWLWKKKEAKsffGQKWKKYWFVLKGSSLYWYSNQQDEKAEGFINLPDFKIERASEC---KKKYAFKAC----------- 82

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 578800679  141 trclspqaeHAGVRTYFFSAESPEEQEAWIQAMGEAA 177
Cdd:cd01260    83 ---------HPKIKTFYFAAENLDDMNKWLSKLNMAI 110

Myosin X Pleckstrin homology (PH) domain, repeat 2; MyoX, a MyTH-FERM myosin, is a molecular motor that has crucial functions in the transport and/or tethering of integrins in the actin-based extensions known as filopodia, microtubule binding, and in netrin-mediated axon guidance. It functions as a dimer. MyoX walks on bundles of actin, rather than single filaments, unlike the other unconventional myosins. MyoX is present in organisms ranging from humans to choanoflagellates, but not in Drosophila and Caenorhabditis elegans.MyoX consists of a N-terminal motor/head region, a neck made of 3 IQ motifs, and a tail consisting of a coiled-coil domain, a PEST region, 3 PH domains, a myosin tail homology 4 (MyTH4), and a FERM domain at its very C-terminus. The first PH domain in the MyoX tail is a split-PH domain, interupted by the second PH domain such that PH 1a and PH 1b flanks PH 2. The third PH domain (PH 3) follows the PH 1b domain. This cd 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 578800679   62 KAGWLFKQ-ASSGV---KQWNKRWFVLVDRCLFYYK-DEKEESILGSIpllsfrvaavqpsdNISRKHTFkvtvcwVDEA 136
Cdd:cd13296     1 KSGWLTKKgGGSSTlsrRNWKSRWFVLRDTVLKYYEnDQEGEKLLGTI--------------DIRSAKEI------VDND 60

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 578800679  137 EASSTRCLSPQAehagvRTYFFSAESPEEQEAWIQAM 173
Cdd:cd13296    61 PKENRLSITTEE-----RTYHLVAESPEDASQWVNVL 92

Dual Adaptor for Phosphotyrosine and 3-Phosphoinositides Pleckstrin homology (PH) domain; DAPP1 (also known as PHISH/3' phosphoinositide-interacting SH2 domain-containing protein or Bam32) plays a role in B-cell activation and has potential roles in T-cell and mast cell function. DAPP1 promotes B cell receptor (BCR) induced activation of Rho GTPases Rac1 and Cdc42, which feed into mitogen-activated protein kinases (MAPK) activation pathways and affect cytoskeletal rearrangement. DAPP1can also regulate BCR-induced activation of extracellular signal-regulated kinase (ERK), and c-jun NH2-terminal kinase (JNK). DAPP1 contains an N-terminal SH2 domain and a C-terminal pleckstrin homology (PH) domain with a single tyrosine phosphorylation site located centrally. DAPP1 binds strongly to both PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The PH domain is essential for plasma membrane recruitment of PI3K upon cell activation. 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 578800679   61 TKAGWLFKQASSgVKQWNKRWFVLVDRCLFYYKDEKEESILGSIPLLsfRVAAVQPSDNISRKHTFKVTVCWvdeaeass 140
Cdd:cd10573     4 SKEGYLTKLGGI-VKNWKTRWFVLRRNELKYFKTRGDTKPIRVLDLR--ECSSVQRDYSQGKVNCFCLVFPE-------- 72

                          90       100       110
                  ....*....|....*....|....*....|
gi 578800679  141 trclspqaehagvRTYFFSAESPEEQEAWI 170
Cdd:cd10573    73 -------------RTFYMYANTEEEADEWV 89

Evectin Pleckstrin homology (PH) domain; There are 2 members of the evectin family (also called pleckstrin homology domain containing, family B): evt-1 (also called PLEKHB1) and evt-2 (also called PLEKHB2). evt-1 is specific to the nervous system, where it is expressed in photoreceptors and myelinating glia. evt-2 is widely expressed in both neural and nonneural tissues. Evectins possess a single N-terminal PH domain and a C-terminal hydrophobic region. evt-1 is thought to function as a mediator of post-Golgi trafficking in cells that produce large membrane-rich organelles. It is a candidate gene for the inherited human retinopathy autosomal dominant familial exudative vitreoretinopathy and a susceptibility gene for multiple sclerosis. evt-2 is essential for retrograde endosomal membrane transport from the plasma membrane (PM) to the Golgi. Two membrane trafficking pathways pass through recycling endosomes: a recycling pathway and a retrograde pathway that links the PM to the Golgi/ER. Its PH domain that is unique in that it specifically recognizes phosphatidylserine (PS), but not polyphosphoinositides. PS is an anionic phospholipid class in eukaryotic biomembranes, is highly enriched in the PM, and plays key roles in various physiological processes such as the coagulation cascade, recruitment and activation of signaling molecules, and clearance of apoptotic cells. PH domains are only found in eukaryotes. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. 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 578800679   59 PVTKAGWLFKQaSSGVKQWNKRWFVL-VDRCLFYYKDEKEESILGSIPL----LSFRVAA----VQPSDNISRKHTFKVt 129
Cdd:cd13265     2 ALVKSGWLLRQ-STILKRWKKNWFVLyGDGNLVYYEDETRREVEGRINMprecRNIRVGLecrdVQPPEGRSRDCLLQI- 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 578800679  130 VCwvdeaeasstrclspqaeHAGVRTyFFSAESPEEQEAWIQAMGEA 176
Cdd:cd13265    80 VL------------------RDGSTL-FLCAESADDALAWKLALQDA 107

Rho GTPase activating protein 24 Pleckstrin homology (PH) domain; RhoGap24 (also called ARHGAP24, p73RhoGAp, and Filamin-A-associated RhoGAP) 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. 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 578800679   60 VTKAGWLFKQASSgVKQWNKRWFVLVDRCLFYYKDEKEESILGSIPLLSFRVAAVQPSDNISRKHTFKVtVCWVDEAEAS 139
Cdd:cd13379     3 VIKCGWLRKQGGF-VKTWHTRWFVLKGDQLYYFKDEDETKPLGTIFLPGNRVTEHPCNEEEPGKFLFEV-VPGGDRERMT 80

                          90       100       110
                  ....*....|....*....|....*....|....
gi 578800679  140 STRclspqaehagvRTYFFSAESPEEQEAWIQAM 173
Cdd:cd13379    81 ANH-----------ETYLLMASTQNDMEDWVKSI 103

Anillin Pleckstrin homology (PH) domain; Anillin (Rhotekin/RTKN; also called PLEKHK/Pleckstrin homology domain-containing family K) is an actin binding protein involved in cytokinesis. It interacts with GTP-bound Rho proteins and results in the inhibition of their GTPase activity. Dysregulation of the Rho signal transduction pathway has been implicated in many forms of cancer. Anillin proteins have a N-terminal HRI domain/ACC (anti-parallel coiled-coil) finger domain or Rho-binding domain binds small GTPases from the Rho family. The C-terminal PH domain helps target anillin to ectopic septin containing foci. 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 578800679   71 SSGVKQWNKRWFVLVDRCLFYYK---DEKEESILGSIPLLSFRVAAVQPSDNI--SRKHTFKVtVCWVDeaeasstRCLS 145
Cdd:cd01263    14 VSGLGAWHRRWCVLRGGYLSFWKypdDEEKKKPIGSIDLTKCITEKVEPAPRElcARPNTFLL-ETLRP-------AEDD 85

                          90       100       110
                  ....*....|....*....|....*....|.
gi 578800679  146 PQAEHAGVRTYFFSAESPEEQEAWIQAMGEA 176
Cdd:cd01263    86 DRDDTNEKIRVLLSADTKEERIEWLSALNQT 116

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 2; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the second PH domain 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 578800679   62 KAGWLFKqasSGVKQ---WNKRWFVLVDRCLFYYKD-----EKEESILGSiPLLSFRVAAVQPsDNISRKHTFKVTVcwv 133
Cdd:cd01251     4 KEGYLEK---TGPKQtdgFRKRWFTLDDRRLMYFKDpldafPKGEIFIGS-KEEGYSVREGLP-PGIKGHWGFGFTL--- 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 578800679  134 deaeasstrclspqaeHAGVRTYFFSAESPEEQEAWIQAMGEA 176
Cdd:cd01251    76 ----------------VTPDRTFLLSAETEEERREWITAIQKV 102

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 578800679   61 TKAGWLFKQASSGVKqWNKRWFVLVDRCLFYYKDEKEESILGSIPL---LSFRVAAVQPS----DNISRKHTFKVTVcwv 133
Cdd:cd13261     6 TKRGYLSKKTSDSGK-WHERWFALYQNLLFYFENESSSRPSGLYLLegcYCERLPTPKGAlkgkDHLEKQHYFTISF--- 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 578800679  134 deaeasstrclspqaEHAGVRTYFFSAESPEEQEAWIQAMGEA 176
Cdd:cd13261    82 ---------------RHENQRQYELRAETESDCDEWVEAIKQA 109

Pleckstrin homology (PH) domain; Budding yeast contain two main p21-activated kinases (PAKs), Cla4 and Ste20. The yeast Ste20 protein kinase is involved in pheromone response, though the function of Ste20 mammalian homologs is unknown. Cla4 is involved in budding and cytokinesis and interacts with Cdc42, a GTPase required for polarized cell growth as is Pak. Cla4 and Ste20 kinases share a function in localizing cell growth with respect to the septin ring. They both contain a PH domain, a Cdc42/Rac interactive binding (CRIB) domain, and a C-terminal Protein Kinase catalytic (PKc) 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 578800679   60 VTKAGWLFkqassgVKQ-------WNKRWFVLVDRCLFYYKDEKEESILGSIPLLSfrVAAVQPSDNisRKHTFKVTVCw 132
Cdd:cd13279     1 VVKSGWVS------VKEdgllsfrWSKRYLVLREQSLDFYKNESSSSASLSIPLKD--ISNVSRTDL--KPYCFEIVRK- 69

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 578800679  133 vdeaeasstrclspqaehAGVRTYFFSAESPEEQEAWI 170
Cdd:cd13279    70 ------------------SSTKSIYISVKSDDELYDWM 89

Pleckstrin 2 Pleckstrin homology (PH) domain, repeat 1; Pleckstrin is a protein found in platelets. This name is derived from platelet and leukocyte C kinase substrate and the KSTR string of amino acids. Pleckstrin 2 contains two PH domains and a DEP (dishvelled, egl-10, and pleckstrin) domain. Unlike pleckstrin 1, pleckstrin 2 does not contain obvious sites of PKC phosphorylation. Pleckstrin 2 plays a role in actin rearrangement, large lamellipodia and peripheral ruffle formation, and may help orchestrate cytoskeletal arrangement. The PH domains of pleckstrin 2 are thought to contribute to lamellipodia formation. This cd contains the first PH domain 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 578800679   60 VTKAGWLFKQASSgVKQWNKRWFVLVDRCLFYYKDEKEESILGSIPLL-SFRVAAVQPSDNisRKHTFKVTVcwvdeaea 138
Cdd:cd13301     3 IIKEGYLVKKGHV-VNNWKARWFVLKEDGLEYYKKKTDSSPKGMIPLKgCTITSPCLEYGK--RPLVFKLTT-------- 71

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 578800679  139 sstrclSPQAEHagvrtyFFSAESPEEQEAWIQAMGEAAR 178
Cdd:cd13301    72 ------AKGQEH------FFQACSREERDAWAKDITKAIT 99

Src kinase-associated phosphoprotein homolog and Skap 2 Pleckstrin homology (PH) domain; Adaptor protein Skap-hom, a homolog of Skap55, which interacts with actin and with ADAP (adhesion and degranulation promoting adapter protein) undergoes tyrosine phosphorylation in response to plating of bone marrow-derived macrophages on fibronectin. Skap-hom has an N-terminal coiled-coil conformation that is involved in homodimer formation, a central PH domain and a C-terminal SH3 domain that associates with ADAP. The Skap-hom PH domain regulates intracellular targeting; its interaction with the DM domain inhibits Skap-hom actin-based ruffles in macrophages and its binding to 3'-phosphoinositides reverses this autoinhibition. The Skap-hom PH domain binds PI[3,4]P2 and PI[3,4,5]P3, but not to PI[3]P, PI[5]P, or PI[4,5]P2. Skap2 is a downstream target of Heat shock transcription factor 4 (HSF4) and functions in the regulation of actin reorganization during lens differentiation. It is thought that SKAP2 anchors the complex of tyrosine kinase adaptor protein 2 (NCK20/focal adhesion to fibroblast growth factor receptors at the lamellipodium in lens epithelial cells. Skap2 has an N-terminal coiled-coil conformation which interacts with the SH2 domain of NCK2, a central PH domain and a C-terminal SH3 domain that associates with ADAP (adhesion and degranulation promoting adapter protein)/FYB (the Fyn binding protein). Skap2 PH domain binds to membrane lipids. Skap adaptor proteins couple receptors to cytoskeletal rearrangements. Src kinase-associated phosphoprotein of 55 kDa (Skap55)/Src kinase-associated phosphoprotein 1 (Skap1), Skap2, and Skap-hom have an N-terminal coiled-coil conformation, a central PH domain and a C-terminal SH3 domain. Their PH domains bind 3'-phosphoinositides as well as directly affecting targets such as in Skap55 where it directly affecting integrin regulation by ADAP and NF-kappaB activation or in Skap-hom where the dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch that controls ruffle formation. 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 578800679   60 VTKAGWLFKQA---SSGVKQWNKRWFVLVDRCLFYYKDEKEESILGSIPLLSFRVAAvqpsDNISRKHTfKVTVCWvdea 136
Cdd:cd13381     1 VLKAGYLEKRRkdhSFFGFEWQKRWCALSNSVFYYYGSDKDKQQKGEFAIDGYDVKM----NNTLRKDA-KKDCCF---- 71

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 578800679  137 easstRCLSPQAehagvRTYFFSAESPEEQEAWIQAM 173
Cdd:cd13381    72 -----EICAPDK-----RVYQFTAASPKEAEEWVQQI 98