Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302 411 DTRQRQEWTAAIQmAIRLQAEGKKSLHKDLKQKRREQREQRERRRAAKEEELLRLQQLQEEKERKLQELELLQEAQRQAE 490
Cdd:COG1196  223 KELEAELLLLKLR-ELEAELEELEAELEELEAELEELEAELAELEAELEELRLELEELELELEEAQAEEYELLAELARLE 301

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302 491 RLLQEEEERRRSQHRELQQaLEGQLREAEQARASMQAEMELKEEEAARQRQRIKELEEM----QQRLQEALQLEVKARRD 566
Cdd:COG1196  302 QDIARLEERRRELEERLEE-LEEELAELEEELEELEEELEELEEELEEAEEELEEAEAElaeaEEALLEAEAELAEAEEE 380

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302 567 EESVRLAQTRLLEEEEEKLKQLMQLKEEQERY---IERAQQEKEELQQEMAQQSRSLQQAQQQLEEVRQNRQRADEDVEA 643
Cdd:COG1196  381 LEELAEELLEALRAAAELAAQLEELEEAEEALlerLERLEEELEELEEALAELEEEEEEEEEALEEAAEEEAELEEEEEA 460

                 ....*...
gi 795201302 644 AQRKLRQA 651
Cdd:COG1196  461 LLELLAEL 468

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 795201302   332 VLKQGYLWKRG-HLRRNWTERWFQLQPSCLCYFGSEECKEK---RGIIPLDAHCCVEVL-PDRDGKRCMFCVKTATR-TY 405
Cdd:smart00233   1 VIKEGWLYKKSgGGKKSWKKRYFVLFNSTLLYYKSKKDKKSykpKGSIDLSGCTVREAPdPDSSKKPHCFEIKTSDRkTL 80

                           90       100
                   ....*....|....*....|..
gi 795201302   406 EMSASDTRQRQEWTAAIQMAIR 427
Cdd:smart00233  81 LLQAESEEEREKWVEALRKAIA 102

Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302 411 DTRQRQEWTAAIQmAIRLQAEGKKSLHKDLKQKRREQREQRERRRAAKEEELLRLQQLQEEKERKLQELELLQEAQRQAE 490
Cdd:COG1196  223 KELEAELLLLKLR-ELEAELEELEAELEELEAELEELEAELAELEAELEELRLELEELELELEEAQAEEYELLAELARLE 301

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302 491 RLLQEEEERRRSQHRELQQaLEGQLREAEQARASMQAEMELKEEEAARQRQRIKELEEM----QQRLQEALQLEVKARRD 566
Cdd:COG1196  302 QDIARLEERRRELEERLEE-LEEELAELEEELEELEEELEELEEELEEAEEELEEAEAElaeaEEALLEAEAELAEAEEE 380

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302 567 EESVRLAQTRLLEEEEEKLKQLMQLKEEQERY---IERAQQEKEELQQEMAQQSRSLQQAQQQLEEVRQNRQRADEDVEA 643
Cdd:COG1196  381 LEELAEELLEALRAAAELAAQLEELEEAEEALlerLERLEEELEELEEALAELEEEEEEEEEALEEAAEEEAELEEEEEA 460

                 ....*...
gi 795201302 644 AQRKLRQA 651
Cdd:COG1196  461 LLELLAEL 468

chromosome segregation protein SMC, primarily archaeal type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. It is found in a single copy and is homodimeric in prokaryotes, but six paralogs (excluded from this family) are found in eukarotes, where SMC proteins are heterodimeric. This family represents the SMC protein of archaea and a few bacteria (Aquifex, Synechocystis, etc); the SMC of other bacteria is described by TIGR02168. The N- and C-terminal domains of this protein are well conserved, but the central hinge region is skewed in composition and highly divergent. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302   459 EEELLRLQQLQEEKERKLQELELLQEAQRQAERLLQEEEERRRSQHRELQQALEG-QLREAEQARASMQAEMELKEEEAA 537
Cdd:TIGR02169  729 EQEEEKLKERLEELEEDLSSLEQEIENVKSELKELEARIEELEEDLHKLEEALNDlEARLSHSRIPEIQAELSKLEEEVS 808

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302   538 RQRQRIKELEEMQQRLQEALQLEVKARRDEESVRLAQTRLLEEEEEKLKQLMQLKEEQERYIERAQQEKEELQQEMaqqs 617
Cdd:TIGR02169  809 RIEARLREIEQKLNRLTLEKEYLEKEIQELQEQRIDLKEQIKSIEKEIENLNGKKEELEEELEELEAALRDLESRL---- 884

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*...
gi 795201302   618 rslqqaqqqlEEVRQNRQRADEDVEAAQRKLRQASTNVKHWNVQMNRL 665
Cdd:TIGR02169  885 ----------GDLKKERDELEAQLRELERKIEELEAQIEKKRKRLSEL 922

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 795201302   332 VLKQGYLWKRG-HLRRNWTERWFQLQPSCLCYFGSEECKEK---RGIIPLDAHCCVEVL-PDRDGKRCMFCVKTATR-TY 405
Cdd:smart00233   1 VIKEGWLYKKSgGGKKSWKKRYFVLFNSTLLYYKSKKDKKSykpKGSIDLSGCTVREAPdPDSSKKPHCFEIKTSDRkTL 80

                           90       100
                   ....*....|....*....|..
gi 795201302   406 EMSASDTRQRQEWTAAIQMAIR 427
Cdd:smart00233  81 LLQAESEEEREKWVEALRKAIA 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 795201302 334 KQGYLWKRGH-LRRNWTERWFQLQPSCLCYFGSEE--CKEKRGIIPLDAHCCVEVLPDRDGKRCmFCVKTAT-RTYEMSA 409
Cdd:cd00821    1 KEGYLLKRGGgGLKSWKKRWFVLFEGVLLYYKSKKdsSYKPKGSIPLSGILEVEEVSPKERPHC-FELVTPDgRTYYLQA 79

                         90
                 ....*....|...
gi 795201302 410 SDTRQRQEWTAAI 422
Cdd:cd00821   80 DSEEERQEWLKAL 92

General Receptor for Phosphoinositides-1-like Pleckstrin homology (PH) domain; GRP1/cytohesin3 and the related proteins ARNO (ARF nucleotide-binding site opener)/cytohesin-2 and cytohesin-1 are ARF exchange factors that contain a pleckstrin homology (PH) domain thought to target these proteins to cell membranes through binding polyphosphoinositides. The PH domains of all three proteins exhibit relatively high affinity for PtdIns(3,4,5)P3. Within the Grp1 family, diglycine (2G) and triglycine (3G) splice variants, differing only in the number of glycine residues in the PH domain, strongly influence the affinity and specificity for phosphoinositides. The 2G variants selectively bind PtdIns(3,4,5)P3 with high affinity,the 3G variants bind PtdIns(3,4,5)P3 with about 30-fold lower affinity and require the polybasic region for plasma membrane targeting. These ARF-GEFs share a common, tripartite structure consisting of an N-terminal coiled-coil domain, a central domain with homology to the yeast protein Sec7, a PH domain, and a C-terminal polybasic region. The Sec7 domain is autoinhibited by conserved elements proximal to the PH domain. GRP1 binds to the DNA binding domain of certain nuclear receptors (TRalpha, TRbeta, AR, ER, but not RXR), and can repress thyroid hormone receptor (TR)-mediated transactivation by decreasing TR-complex formation on thyroid hormone response elements. ARNO promotes sequential activation of Arf6, Cdc42 and Rac1 and insulin secretion. Cytohesin acts as a PI 3-kinase effector mediating biological responses including cell spreading and adhesion, chemotaxis, protein trafficking, and cytoskeletal rearrangements, only some of which appear to depend on their ability to activate ARFs. 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 795201302 332 VLKQGYLWKRGHLRRNWTERWFQLQPSCLCYFGSEECKEKRGIIPLDAhccVEVLPDRDGKRcMFC-------------- 397
Cdd:cd01252    3 PDREGWLLKLGGRVKSWKRRWFILTDNCLYYFEYTTDKEPRGIIPLEN---LSVREVEDKKK-PFCfelyspsngqvika 78

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 795201302 398 VKTATR---------TYEMSASDTRQRQEWTAAIQMAI 426
Cdd:cd01252   79 CKTDSDgkvvegnhtVYRISAASEEERDEWIKSIKASI 116

Sesquipedalian family Pleckstrin homology (PH) domain; The sesquipedalian family has 2 mammalian members: Ses1 and Ses2, which are also callled 7 kDa inositol polyphosphate phosphatase-interacting protein 1 and 2. They play a role in endocytic trafficking and are required for receptor recycling from endosomes, both to the trans-Golgi network and the plasma membrane. Members of this family form homodimers and heterodimers. Sesquipedalian interacts with inositol polyphosphate 5-phosphatase OCRL-1 (INPP5F) also known as Lowe oculocerebrorenal syndrome protein, a phosphatase enzyme that is involved in actin polymerization and is found in the trans-Golgi network and INPP5B. Sesquipedalian contains a single 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 795201302 334 KQGYLWKRGHLRRNWTERWFQLQPSCLCYFGSEECKEKRGIIPLDahCCVEVLPDRDGKRCmFCVKTA---TRTYEMSAS 410
Cdd:cd13288   10 KEGYLWKKGERNTSYQKRWFVLKGNLLFYFEKKGDREPLGVIVLE--GCTVELAEDAEPYA-FAIRFDgpgARSYVLAAE 86

                         90
                 ....*....|....*
gi 795201302 411 DTRQRQEWTAAIQMA 425
Cdd:cd13288   87 NQEDMESWMKALSRA 101

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 795201302 334 KQGYLWKRGHLRRNWTERWFQLQPSCLCYFGSEE--CKEKRGIIPLDAHCcvEVLPDRDGkrCMFCVKTATRTYEMSASD 411
Cdd:cd13282    1 KAGYLTKLGGKVKTWKRRWFVLKNGELFYYKSPNdvIRKPQGQIALDGSC--EIARAEGA--QTFEIVTEKRTYYLTADS 76

                         90
                 ....*....|....*....
gi 795201302 412 TRQRQEWTAAIQMAIRLQA 430
Cdd:cd13282   77 ENDLDEWIRVIQNVLRRQA 95

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 1; ARAP proteins (also called centaurin delta) are phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating proteins that modulate actin cytoskeleton remodeling by regulating ARF and RHO family members. They bind phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4,5)P2) binding. There are 3 mammalian ARAP proteins: ARAP1, ARAP2, and ARAP3. All ARAP proteins contain a N-terminal SAM (sterile alpha motif) domain, 5 PH domains, an ArfGAP domain, 2 ankyrin domain, A RhoGap domain, and a Ras-associating domain. This hierarchy contains the first PH domain in ARAP. 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 795201302 333 LKQGYLWKRGHLRRN--WTERWFQLQPSCLCYFGSEECKEKRGIIPLDahCCVEVLPDRDGKrcmFCVKTATRTYEMSAS 410
Cdd:cd13253    1 IKSGYLDKQGGQGNNkgFQKRWVVFDGLSLRYFDSEKDAYSKRIIPLS--AISTVRAVGDNK---FELVTTNRTFVFRAE 75

                         90
                 ....*....|....*....
gi 795201302 411 DTRQRQEWTAAIQMAIRLQ 429
Cdd:cd13253   76 SDDERNLWCSTLQAAISEY 94

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 795201302 334 KQGYLWKRGHLRRNWTERWFQLQPSCLCYFGSEECKEKrgIIPLDAHCCVEVLPDRD-GKRCMFCVKTATRTYEMSASDT 412
Cdd:cd10573    5 KEGYLTKLGGIVKNWKTRWFVLRRNELKYFKTRGDTKP--IRVLDLRECSSVQRDYSqGKVNCFCLVFPERTFYMYANTE 82

                         90
                 ....*....|.
gi 795201302 413 RQRQEWTAAIQ 423
Cdd:cd10573   83 EEADEWVKLLK 93

Tandem PH-domain-containing proteins 1 and 2 Pleckstrin homology (PH) domain, C-terminal repeat; The binding of TAPP1 (also called PLEKHA1/pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 1) and 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). TAPP1 and TAPP2 contain 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. 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 795201302 325 YQELIQDVLKQGYLWKRGHLRRNWTERWFQLQPSCLCYFGSEECKEKRGIIPL-DAHCCVEVLPD----RDGkrcMFCVK 399
Cdd:cd13271    1 RQRAGRNVIKSGYCVKQGAVRKNWKRRFFILDDNTISYYKSETDKEPLRTIPLrEVLKVHECLVKsllmRDN---LFEII 77

                         90       100
                 ....*....|....*....|....*..
gi 795201302 400 TATRTYEMSASDTRQRQEWTAAIQMAI 426
Cdd:cd13271   78 TTSRTFYIQADSPEEMHSWIKAISGAI 104

Arabidopsis thaliana Pleckstrin homolog (PH) 1 (AtPH1) PH domain; AtPH1 is expressed in all plant tissue and is proposed to be the plant homolog of human pleckstrin. Pleckstrin consists of two PH domains separated by a linker region, while AtPH has a single PH domain with a short N-terminal extension. AtPH1 binds PtdIns3P specifically and is thought to be an adaptor molecule since it has no obvious catalytic functions. 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 795201302 334 KQGYLWKRGHLRRNWTERWFQLQPSCLCYFGSEE---CKEKRGIIPLDAHCCVEVLPDRDGKRCMFCVKTATRTYEMSAS 410
Cdd:cd13276    1 KAGWLEKQGEFIKTWRRRWFVLKQGKLFWFKEPDvtpYSKPRGVIDLSKCLTVKSAEDATNKENAFELSTPEETFYFIAD 80

                         90
                 ....*....|....*.
gi 795201302 411 DTRQRQEWTAAIQMAI 426
Cdd:cd13276   81 NEKEKEEWIGAIGRAI 96

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 795201302 334 KQGYLWKRGH-LRRNWTERWFQLQPSCLCYFgseeckeKRGIIPLDAH-------CCVEVLPDRDGKRCmFCVKTATRTY 405
Cdd:cd13250    1 KEGYLFKRSSnAFKTWKRRWFSLQNGQLYYQ-------KRDKKDEPTVmvedlrlCTVKPTEDSDRRFC-FEVISPTKSY 72

                         90       100
                 ....*....|....*....|.
gi 795201302 406 EMSASDTRQRQEWTAAIQMAI 426
Cdd:cd13250   73 MLQAESEEDRQAWIQAIQSAI 93

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 795201302 334 KQGYLWKRGH-----LRRNWTERWFQLQPSCLCYFGSEECKEK-RGIIplDAHCCVEVLpDRDGKRCMFCVKTATRTYEM 407
Cdd:cd13296    1 KSGWLTKKGGgsstlSRRNWKSRWFVLRDTVLKYYENDQEGEKlLGTI--DIRSAKEIV-DNDPKENRLSITTEERTYHL 77

                         90       100
                 ....*....|....*....|
gi 795201302 408 SASDTRQRQEWTAAIQMAIR 427
Cdd:cd13296   78 VAESPEDASQWVNVLTRVIS 97

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 795201302 332 VLKQGYLWKR----GHLRRNWTERWFQLQPSCLCYFGSEECKEKRGIIPLDAH---------------CCVEVL-PDRdg 391
Cdd:cd13381    1 VLKAGYLEKRrkdhSFFGFEWQKRWCALSNSVFYYYGSDKDKQQKGEFAIDGYdvkmnntlrkdakkdCCFEICaPDK-- 78

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 795201302 392 krcmfcvktatRTYEMSASDTRQRQEWTAAIQMAIR 427
Cdd:cd13381   79 -----------RVYQFTAASPKEAEEWVQQIKFILQ 103

Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302 463 LRLQQLQEEKERKLQELELLQEAQRQAErllqeeeerrrsqhrelQQALEGQLREAEQARASMQAEMELKEEEAARQRQR 542
Cdd:COG1196  213 ERYRELKEELKELEAELLLLKLRELEAE-----------------LEELEAELEELEAELEELEAELAELEAELEELRLE 275

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302 543 I----KELEEMQQRLQEALQLEVKARRDEESVRLAQTRLLEEEEEKLKQLMQLKEEQERYIERAQQEKEELQQEMAQQSR 618
Cdd:COG1196  276 LeeleLELEEAQAEEYELLAELARLEQDIARLEERRRELEERLEELEEELAELEEELEELEEELEELEEELEEAEEELEE 355

                        170       180       190
                 ....*....|....*....|....*....|....*
gi 795201302 619 SLQQAQQQLEEVRQNRQRADEDVEAAQRKLRQAST 653
Cdd:COG1196  356 AEAELAEAEEALLEAEAELAEAEEELEELAEELLE 390

Phospholipase D pleckstrin homology (PH) domain; PLD hydrolyzes phosphatidylcholine to phosphatidic acid (PtdOH), which can bind target proteins. PLD contains a PH domain, a PX domain and four conserved PLD signature domains. The PLD PH domain is specific for bisphosphorylated inositides. 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 795201302 334 KQGYLWKRGHLRR-----------------NWTERWFQLQPSCLCYFGSEECKEKRGIIPLDAHCCVEVLPDRD--GKRC 394
Cdd:cd01254   26 KEGYLKKRSGGHRqgwrvchfyccckamcgRWSKRWFIVKDSFLAYVKDPDSGAILDVFLFDQEFKVSRGGKETkyGSRH 105

                         90       100       110
                 ....*....|....*....|....*....|.
gi 795201302 395 MFCVKTATRTYEMSASDTRQRQEWTAAIQMA 425
Cdd:cd01254  106 GLKITNLSRKLKLKCKSERKAKQWVESIEEA 136

Pleckstrin 2 Pleckstrin homology (PH) domain, repeat 2; 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 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 795201302 332 VLKQGYLWKRGHLRRNWTERWFQLQ--PSCLCYFGSEECKEKRGIIPLDAhCCVEVLPDRDGKRC------MFCVKTATR 403
Cdd:cd13302    7 IVKQGCLLKQGHRRKNWKVRKFVLRddPAYLHYYDPAKGEDPLGAIHLRG-CVVTAVEDNSNPRKgsvegnLFEIITADE 85

                         90       100
                 ....*....|....*....|...
gi 795201302 404 T-YEMSASDTRQRQEWTAAIQMA 425
Cdd:cd13302   86 VhYYLQAATPAERTEWIKAIQMA 108

KIFIA and KIFIB protein pleckstrin homology (PH) domain; The kinesin-3 family motors KIFIA (Caenorhabditis elegans homolog unc-104) and KIFIB transport synaptic vesicle precursors that contain synaptic vesicle proteins, such as synaptophysin, synaptotagmin and the small GTPase RAB3A, but they do not transport organelles that contain plasma membrane proteins. They have a N-terminal motor domain, followed by a coiled-coil domain, and a C-terminal PH domain. KIF1A adopts a monomeric form in vitro, but acts as a processive dimer in vivo. KIF1B has alternatively spliced isoforms distinguished by the presence or absence of insertion sequences in the conserved amino-terminal region of the protein; this results in their different motor activities. KIF1A and KIF1B bind to RAB3 proteins through the adaptor protein mitogen-activated protein kinase (MAPK) -activating death domain (MADD; also calledDENN), which was first identified as a RAB3 guanine nucleotide exchange factor (GEF). 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 795201302 332 VLKQGYLWKRGHLRRNWTERWFQLQPSCLCYFGSEECKEKRGIIPLdAHCCVEVLPDRD---GKRCMFCVKTATRTYEMS 408
Cdd:cd01233    6 VSKRGYLLFLEDATDGWVRRWVVLRRPYLHIYSSEKDGDERGVINL-STARVEYSPDQEallGRPNVFAVYTPTNSYLLQ 84

                         90
                 ....*....|....
gi 795201302 409 ASDTRQRQEWTAAI 422
Cdd:cd01233   85 ARSEKEMQDWLYAI 98

Src kinase-associated phosphoprotein 1 Pleckstrin homology (PH) domain; Adaptor protein Skap1 (also called Skap55/Src kinase-associated phosphoprotein of 55 kDa) and its partner, ADAP (adhesion and degranulation promoting adapter protein) help reorganize the cytoskeleton and/or promote integrin-mediated adhesion upon immunoreceptor activation. Skap1 is also involved in T Cell Receptor (TCR)-induced RapL-Rap1 complex formation and LFA-1 activation. Skap1 has an N-terminal coiled-coil conformation which is proposed to be involved in homodimer formation, a central PH domain and a C-terminal SH3 domain that associates with ADAP. The Skap1 PH domain plays a role in controlling integrin function via recruitment of ADAP-SKAP complexes to integrins as well as in controlling the ability of ADAP to interact with the CBM signalosome and regulate NF-kappaB. SKAP1 is necessary for RapL binding to membranes in a PH domain-dependent manner and the PI3K pathway. Skap adaptor proteins couple receptors to cytoskeletal rearrangements. Skap55/Skap1, Skap2, and Skap-homology (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 795201302 332 VLKQGYLWKR----GHLRRNWTERWFQLQPSCLCYFGSEECKEKRGIIPLDAhCCVEVLPD--RDGKR--CMFCVKTATR 403
Cdd:cd13380    1 ILKQGYLEKRskdhSFFGSEWQKRWCVLTNRAFYYYASEKSKQPKGGFLIKG-YSAQMAPHlrKDSRRdsCFELTTPGRR 79

                         90       100
                 ....*....|....*....|....
gi 795201302 404 TYEMSASDTRQRQEWTAAIQMAIR 427
Cdd:cd13380   80 TYQFTAASPSEARDWVDQIQFLLK 103

Human Oxysterol binding protein (OSBP) related proteins 10 and 11 (ORP10 and ORP11) Pleckstrin homology (PH) domain; Human ORP10 is involvedt in intracellular transport or organelle positioning and is proposed to function as a regulator of cellular lipid metabolism. Human ORP11 localizes at the Golgi-late endosome interface and is thought to form a dimer with ORP9 functioning as an intracellular lipid sensor or transporter. Both ORP10 and ORP11 contain a N-terminal PH domain, a FFAT motif (two phenylalanines in an acidic tract), and a C-terminal OSBP-related domain. Oxysterol binding proteins are a multigene family that is conserved in yeast, flies, worms, mammals and plants. In general OSBPs and ORPs have been found to be involved in the transport and metabolism of cholesterol and related lipids in eukaryotes. They all contain a C-terminal oxysterol binding domain, and most contain an N-terminal PH domain. OSBP PH domains bind to membrane phosphoinositides and thus likely play an important role in intracellular targeting. They are members of the oxysterol binding protein (OSBP) family which includes OSBP, OSBP-related proteins (ORP), Goodpasture antigen binding protein (GPBP), and Four phosphate adaptor protein 1 (FAPP1). They have a wide range of purported functions including sterol transport, cell cycle control, pollen development and vessicle transport from Golgi recognize both PI lipids and ARF 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 795201302 336 GYLWKRGHLRRNWTERWFQLQPSC--LCYFGSEECKEK--RGIIPL-DAhccvEVLPDRDGKRcMFCVKTAT-RTYEMSA 409
Cdd:cd13291    3 GQLLKYTNVVKGWQNRWFVLDPDTgiLEYFLSEESKNQkpRGSLSLaGA----VISPSDEDSH-TFTVNAANgEMYKLRA 77

                 ....*....
gi 795201302 410 SDTRQRQEW 418
Cdd:cd13291   78 ADAKERQEW 86

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 795201302 331 DVLKQGYLWKRGHLRRNWTERWFQLQPSCLCYFGSEECKEKRGIIPLDAHCCVEVL---PDRDGKRCM-----FCV---K 399
Cdd:cd13261    4 DGTKRGYLSKKTSDSGKWHERWFALYQNLLFYFENESSSRPSGLYLLEGCYCERLPtpkGALKGKDHLekqhyFTIsfrH 83

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 795201302 400 TATRTYEMSASDTRQRQEWTAAIQMA----IRLQAEG--KKSLH 437
Cdd:cd13261   84 ENQRQYELRAETESDCDEWVEAIKQAsfnkLLLQKEEleQKYLH 127

Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 795201302 409 ASDTRQRQEWTAAIQMAIRLQAEGKKSLHKDLKQKRREQREQRERRRAAKEEELLRLQQLQEEKERKLQELELLQEAQRQ 488
Cdd:COG1196  333 EELEEELEELEEELEEAEEELEEAEAELAEAEEALLEAEAELAEAEEELEELAEELLEALRAAAELAAQLEELEEAEEAL 412