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 297303457 510 SKRRISCKDLGRGDCEGWLWKKKDAKSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRKKYAFK 589
Cdd:cd01260    1 SRRRVSCKDLGRGDCQGWLWKKKEAKSFFGQKWKKYWFVLKGSSLYWYSNQQDEKAEGFINLPDFKIERASECKKKYAFK 80

                         90       100       110
                 ....*....|....*....|....*....|....
gi 297303457 590 ACHPKIKSFYFAAEHLDDMNRWLNRINMLTAGYA 623
Cdd:cd01260   81 ACHPKIKTFYFAAENLDDMNKWLSKLNMAINKYA 114

Connector enhancer of kinase suppressor of ras; The CRIC - Connector enhancer of kinase suppressor of ras - domain functions as a scaffold in several signal cascades and acts on proliferation, differentiation and apoptosis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 297303457   84 NLKTLSHKLNASAKNLQNFITGRRRSGHYDGRTSRKLPNDFLTSVVDLIGAAKSLLAWLDRSPFAAVTDYSVTRNNVIQL 163
Cdd:pfam10534   1 NLQSLTEKLRASAHSLQNIIQSRRRSNSYDGRSSVKPPNDVLSAVVELIAAAKGLLSWLDRYPFSQLNDYSATRNNIIQL 80

                          90
                  ....*....|...
gi 297303457  164 CLELTTIVQQDCT 176
Cdd:pfam10534  81 CLELTTTVQKDLT 93

PDZ domain of connector enhancer of kinase suppressor of ras 1 (CNK1), CNK2, CNK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of CNK1 (also known as connector enhancer of KSR 1 (CNKSR1), CNK homolog protein 1, connector enhancer of KSR-like), CNK2 (also known as CNKSR2, CNK homolog protein 2), and CNK3 (also known as CNKSR3, CNK homolog protein 3, CNKSR family member 3, maguin-like). CNK proteins modulate Ras-mediated signaling, acting downstream of Ras as a scaffold for the Raf/MEK/ERK kinase cascade. They also modulate signaling mediated via Rho family small GTPases, through interactions with various guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and modulate the insulin signaling pathway through interactions with the Arf guanine nucleotide exchange factors. CNK proteins also regulate cell proliferation and migration by acting as scaffolds for the PI3K/Akt and JNK signaling cascades. CNK2 plays a role in the molecular processes that govern morphology of the postsynaptic density (PSD), and influences subcellular localization of the regulatory NCK-interacting kinase TNIK. TNIK binds a region of CNK2 including the PDZ and the DUF domain; this region also binds the kinase MINK1. CNK2 may also influence the membrane localization of MINK1. CNK3 plays a part in transepithelial sodium transport; it coordinates assembly of an epithelial sodium channel (ENaC)-regulatory complex. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This CNK1-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged as beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta- strand F.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 297303457 214 EVIQLANIKPSEGLGMYIKSTYDGLHVITGTTENSPADRCKKIHAGDEVIQVNHQTVPLIPRSPTSSVATPSSTISTPTK 293
Cdd:cd06748    1 ELVQLTNKKPEEGLGLEIKSTYNGLHVITGTKENSPADRCGKIHAGDEVIQVNYQTVVGWQLKNLVRALREDPHGVTLTL 80

                 .
gi 297303457 294 R 294
Cdd:cd06748   81 K 81

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 297303457 510 SKRRISCKDLGRGDCEGWLWKKKDAKSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRKKYAFK 589
Cdd:cd01260    1 SRRRVSCKDLGRGDCQGWLWKKKEAKSFFGQKWKKYWFVLKGSSLYWYSNQQDEKAEGFINLPDFKIERASECKKKYAFK 80

                         90       100       110
                 ....*....|....*....|....*....|....
gi 297303457 590 ACHPKIKSFYFAAEHLDDMNRWLNRINMLTAGYA 623
Cdd:cd01260   81 ACHPKIKTFYFAAENLDDMNKWLSKLNMAINKYA 114

Connector enhancer of kinase suppressor of ras; The CRIC - Connector enhancer of kinase suppressor of ras - domain functions as a scaffold in several signal cascades and acts on proliferation, differentiation and apoptosis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 297303457   84 NLKTLSHKLNASAKNLQNFITGRRRSGHYDGRTSRKLPNDFLTSVVDLIGAAKSLLAWLDRSPFAAVTDYSVTRNNVIQL 163
Cdd:pfam10534   1 NLQSLTEKLRASAHSLQNIIQSRRRSNSYDGRSSVKPPNDVLSAVVELIAAAKGLLSWLDRYPFSQLNDYSATRNNIIQL 80

                          90
                  ....*....|...
gi 297303457  164 CLELTTIVQQDCT 176
Cdd:pfam10534  81 CLELTTTVQKDLT 93

PDZ domain of connector enhancer of kinase suppressor of ras 1 (CNK1), CNK2, CNK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of CNK1 (also known as connector enhancer of KSR 1 (CNKSR1), CNK homolog protein 1, connector enhancer of KSR-like), CNK2 (also known as CNKSR2, CNK homolog protein 2), and CNK3 (also known as CNKSR3, CNK homolog protein 3, CNKSR family member 3, maguin-like). CNK proteins modulate Ras-mediated signaling, acting downstream of Ras as a scaffold for the Raf/MEK/ERK kinase cascade. They also modulate signaling mediated via Rho family small GTPases, through interactions with various guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and modulate the insulin signaling pathway through interactions with the Arf guanine nucleotide exchange factors. CNK proteins also regulate cell proliferation and migration by acting as scaffolds for the PI3K/Akt and JNK signaling cascades. CNK2 plays a role in the molecular processes that govern morphology of the postsynaptic density (PSD), and influences subcellular localization of the regulatory NCK-interacting kinase TNIK. TNIK binds a region of CNK2 including the PDZ and the DUF domain; this region also binds the kinase MINK1. CNK2 may also influence the membrane localization of MINK1. CNK3 plays a part in transepithelial sodium transport; it coordinates assembly of an epithelial sodium channel (ENaC)-regulatory complex. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This CNK1-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged as beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta- strand F.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 297303457 214 EVIQLANIKPSEGLGMYIKSTYDGLHVITGTTENSPADRCKKIHAGDEVIQVNHQTVPLIPRSPTSSVATPSSTISTPTK 293
Cdd:cd06748    1 ELVQLTNKKPEEGLGLEIKSTYNGLHVITGTKENSPADRCGKIHAGDEVIQVNYQTVVGWQLKNLVRALREDPHGVTLTL 80

                 .
gi 297303457 294 R 294
Cdd:cd06748   81 K 81

SAM domain (Sterile alpha motif); It has been suggested that SAM is an evolutionarily conserved protein binding domain that is involved in the regulation of numerous developmental processes in diverse eukaryotes. The SAM domain can potentially function as a protein interaction module through its ability to homo- and heterooligomerise with other SAM domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 297303457    9 SKWSPSQVVDWMKGLDdcLQQYIKNFEREKISGDQLLRITHQELEDLGVSRIGHQELILEAVDLL 73
Cdd:pfam00536   1 DGWSVEDVGEWLESIG--LGQYIDSFRAGYIDGDALLQLTEDDLLKLGVTLLGHRKKILYAIQRL 63

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 297303457  524 CEGWLWKKKdakSYFSQKWKKYWFVLKDASLYWY---INEEDEKAEGFISLPEFKIDRASECR---KKYAFKACHPKI-- 595
Cdd:pfam00169   3 KEGWLLKKG---GGKKKSWKKRYFVLFDGSLLYYkddKSGKSKEPKGSISLSGCEVVEVVASDspkRKFCFELRTGERtg 79

                          90       100
                  ....*....|....*....|....*.
gi 297303457  596 -KSFYFAAEHLDDMNRWLNRINMLTA 620
Cdd:pfam00169  80 kRTYLLQAESEEERKDWIKAIQSAIR 105

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 297303457 510 SKRRISCKDLGRGDCEGWLWKKKDAKSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRKKYAFK 589
Cdd:cd01260    1 SRRRVSCKDLGRGDCQGWLWKKKEAKSFFGQKWKKYWFVLKGSSLYWYSNQQDEKAEGFINLPDFKIERASECKKKYAFK 80

                         90       100       110
                 ....*....|....*....|....*....|....
gi 297303457 590 ACHPKIKSFYFAAEHLDDMNRWLNRINMLTAGYA 623
Cdd:cd01260   81 ACHPKIKTFYFAAENLDDMNKWLSKLNMAINKYA 114

Connector enhancer of kinase suppressor of ras; The CRIC - Connector enhancer of kinase suppressor of ras - domain functions as a scaffold in several signal cascades and acts on proliferation, differentiation and apoptosis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 297303457   84 NLKTLSHKLNASAKNLQNFITGRRRSGHYDGRTSRKLPNDFLTSVVDLIGAAKSLLAWLDRSPFAAVTDYSVTRNNVIQL 163
Cdd:pfam10534   1 NLQSLTEKLRASAHSLQNIIQSRRRSNSYDGRSSVKPPNDVLSAVVELIAAAKGLLSWLDRYPFSQLNDYSATRNNIIQL 80

                          90
                  ....*....|...
gi 297303457  164 CLELTTIVQQDCT 176
Cdd:pfam10534  81 CLELTTTVQKDLT 93

PDZ domain of connector enhancer of kinase suppressor of ras 1 (CNK1), CNK2, CNK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of CNK1 (also known as connector enhancer of KSR 1 (CNKSR1), CNK homolog protein 1, connector enhancer of KSR-like), CNK2 (also known as CNKSR2, CNK homolog protein 2), and CNK3 (also known as CNKSR3, CNK homolog protein 3, CNKSR family member 3, maguin-like). CNK proteins modulate Ras-mediated signaling, acting downstream of Ras as a scaffold for the Raf/MEK/ERK kinase cascade. They also modulate signaling mediated via Rho family small GTPases, through interactions with various guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and modulate the insulin signaling pathway through interactions with the Arf guanine nucleotide exchange factors. CNK proteins also regulate cell proliferation and migration by acting as scaffolds for the PI3K/Akt and JNK signaling cascades. CNK2 plays a role in the molecular processes that govern morphology of the postsynaptic density (PSD), and influences subcellular localization of the regulatory NCK-interacting kinase TNIK. TNIK binds a region of CNK2 including the PDZ and the DUF domain; this region also binds the kinase MINK1. CNK2 may also influence the membrane localization of MINK1. CNK3 plays a part in transepithelial sodium transport; it coordinates assembly of an epithelial sodium channel (ENaC)-regulatory complex. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This CNK1-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged as beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta- strand F.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 297303457 214 EVIQLANIKPSEGLGMYIKSTYDGLHVITGTTENSPADRCKKIHAGDEVIQVNHQTVPLIPRSPTSSVATPSSTISTPTK 293
Cdd:cd06748    1 ELVQLTNKKPEEGLGLEIKSTYNGLHVITGTKENSPADRCGKIHAGDEVIQVNYQTVVGWQLKNLVRALREDPHGVTLTL 80

                 .
gi 297303457 294 R 294
Cdd:cd06748   81 K 81

Phosphoinositol 3-phosphate binding proteins 1, 2, and 3 pleckstrin homology (PH) domain; PEPP1 (also called PLEKHA4/PH domain-containing family A member 4 and RHOXF1/Rhox homeobox family member 1), and related homologs PEPP2 (also called PLEKHA5/PH domain-containing family A member 5) and PEPP3 (also called PLEKHA6/PH domain-containing family A member 6), have PH domains that interact specifically with PtdIns(3,4)P3. Other proteins that bind PtdIns(3,4)P3 specifically are: TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns3P AtPH1, and Ptd- Ins(3,5)P2 (centaurin-beta2). All of these proteins contain at least 5 of the 6 conserved amino acids that make up the putative phosphatidylinositol 3,4,5- trisphosphate-binding motif (PPBM) located at their N-terminus. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 297303457 523 DCEGWLWKKkdAKSYFSQkWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRAS---ECRKKYAFKACHPKIKSFY 599
Cdd:cd13248    8 VMSGWLHKQ--GGSGLKN-WRKRWFVLKDNCLYYYKDPEEEKALGSILLPSYTISPAPpsdEISRKFAFKAEHANMRTYY 84

                         90
                 ....*....|....*..
gi 297303457 600 FAAEHLDDMNRWLNRIN 616
Cdd:cd13248   85 FAADTAEEMEQWMNAMS 101

SAM domain (Sterile alpha motif); It has been suggested that SAM is an evolutionarily conserved protein binding domain that is involved in the regulation of numerous developmental processes in diverse eukaryotes. The SAM domain can potentially function as a protein interaction module through its ability to homo- and heterooligomerise with other SAM domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 297303457    9 SKWSPSQVVDWMKGLDdcLQQYIKNFEREKISGDQLLRITHQELEDLGVSRIGHQELILEAVDLL 73
Cdd:pfam00536   1 DGWSVEDVGEWLESIG--LGQYIDSFRAGYIDGDALLQLTEDDLLKLGVTLLGHRKKILYAIQRL 63

Boi family Pleckstrin homology domain; Yeast Boi proteins Boi1 and Boi2 are functionally redundant and important for cell growth with Boi mutants displaying defects in bud formation and in the maintenance of cell polarity.They appear to be linked to Rho-type GTPase, Cdc42 and Rho3. Boi1 and Boi2 display two-hybrid interactions with the GTP-bound ("active") form of Cdc42, while Rho3 can suppress of the lethality caused by deletion of Boi1 and Boi2. These findings suggest that Boi1 and Boi2 are targets of Cdc42 that promote cell growth in a manner that is regulated by Rho3. Boi proteins contain a N-terminal SH3 domain, followed by a SAM (sterile alpha motif) domain, a proline-rich region, which mediates binding to the second SH3 domain of Bem1, and C-terminal PH domain. The PH domain is essential for its function in cell growth and is important for localization to the bud, while the SH3 domain is needed for localization to the neck. 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 297303457 523 DCEGWLWKKKDAKSyfsqKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRK---KYAFKACHPKI-KSF 598
Cdd:cd13316    1 DHSGWMKKRGERYG----TWKTRYFVLKGTRLYYLKSENDDKEKGLIDLTGHRVVPDDSNSPfrgSYGFKLVPPAVpKVH 76

                         90
                 ....*....|....*
gi 297303457 599 YFAAEHLDDMNRWLN 613
Cdd:cd13316   77 YFAVDEKEELREWMK 91

SAM (Sterile alpha motif ); SAM (Sterile Alpha Motif) domain is a module consisting of approximately 70 amino acids. This domain is found in the Fungi/Metazoa group and in a restricted number of bacteria. Proteins with SAM domains are represented by a wide variety of domain architectures and have different intracellular localization, including nucleus, cytoplasm and membranes. SAM domains have diverse functions. They can interact with proteins, RNAs and membrane lipids, contain site of phosphorylation and/or kinase docking site, and play a role in protein homo and hetero dimerization/oligomerization in processes ranging from signal transduction to regulation of transcription. Mutations in SAM domains have been linked to several diseases.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 297303457  15 QVVDWMKGLDdcLQQYIKNFEREKISGDQLLRITHQELEDLGVSRIGHQELILEAVD 71
Cdd:cd09487    1 DVAEWLESLG--LEQYADLFRKNEIDGDALLLLTDEDLKELGITSPGHRKKILRAIQ 55

SAM domain (Sterile alpha motif);

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 297303457   11 WSPSQVVDWMKGLDdcLQQYIKNFEREKISG-DQLLRITHQELEDLGVSRIGHQELILEAVDLL 73
Cdd:pfam07647   4 WSLESVADWLRSIG--LEQYTDNFRDQGITGaELLLRLTLEDLKRLGITSVGHRRKILKKIQEL 65

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 297303457 526 GWLWKKKDAKSYFSQK-WKKYWFVLKDASLYWYIN-EEDEKAEGFISLPEFK--IDRASecrKKYAFKACHPKiKSFYFA 601
Cdd:cd13296    3 GWLTKKGGGSSTLSRRnWKSRWFVLRDTVLKYYENdQEGEKLLGTIDIRSAKeiVDNDP---KENRLSITTEE-RTYHLV 78

                         90
                 ....*....|....*
gi 297303457 602 AEHLDDMNRWLNRIN 616
Cdd:cd13296   79 AESPEDASQWVNVLT 93

Src kinase-associated phosphoprotein family Pleckstrin homology (PH) domain; 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-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 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 297303457 525 EGWLWKKKDAKSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRKK----YAFKACHPKIKSFYF 600
Cdd:cd13266    4 AGYLEKRRKDHSFFGSEWQKRWCAISKNVFYYYGSDKDKQQKGEFAINGYDVRMNPTLRKDgkkdCCFELVCPDKRTYQF 83

                         90
                 ....*....|....*...
gi 297303457 601 AAEHLDDMNRWLNRINML 618
Cdd:cd13266   84 TAASPEDAEDWVDQISFI 101

SAM domain of Shank1,2,3 family proteins; SAM (sterile alpha motif) domain of Shank1,2,3 family proteins is a protein-protein interaction domain. Shank1,2,3 proteins are scaffold proteins that are known to interact with a variety of cytoplasmic and membrane proteins. SAM domains of the Shank1,2,3 family are prone to homooligomerization. They are highly enriched in the postsynaptic density, acting as scaffolds to organize assembly of postsynaptic proteins. SAM domains of Shank3 proteins can form large sheets of helical fibers. Shank genes show distinct patterns of expression, in rat Shank1 mRNA is found almost exclusively in brain, Shank2 in brain, kidney and liver, and Shank3 in heart, brain and spleen.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 297303457   7 PVSKWSPSQVVDWMKGLDdcLQQYIKNFEREKISGDQLLRITHQELEDLGVSRIGHQELILEA 69
Cdd:cd09506    1 PVHEWTVDDVGDWLESLN--LGEHRERFMDNEIDGSHLPNLDKEDLTELGVTRVGHRMNIERA 61

Grb2-associated binding protein family Pleckstrin homology (PH) domain; Gab proteins are scaffolding adaptor proteins, which possess N-terminal PH domains and a C-terminus with proline-rich regions and multiple phosphorylation sites. Following activation of growth factor receptors, Gab proteins are tyrosine phosphorylated and activate PI3K, which generates 3-phosphoinositide lipids. By binding to these lipids via the PH domain, Gab proteins remain in proximity to the receptor, leading to further signaling. While not all Gab proteins depend on the PH domain for recruitment, it is required for Gab activity. There are 3 families: Gab1, Gab2, and Gab3. 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 297303457 524 CEGWLWKKKDAKSYFSQKWKKYWFVLKDAS-------LYWYINEEDEKAEGFISLPEFKIDRAS------ECRKKYAFKA 590
Cdd:cd13324    3 YEGWLTKSPPEKKIWRAAWRRRWFVLRSGRlsggqdvLEYYTDDHCKKLKGIIDLDQCEQVDAGltfekkKFKNQFIFDI 82

                         90       100
                 ....*....|....*....|....*
gi 297303457 591 CHPKiKSFYFAAEHLDDMNRWLNRI 615
Cdd:cd13324   83 RTPK-RTYYLVAETEEEMNKWVRCI 106

Grb2-associated binding protein family pleckstrin homology (PH) domain; The Gab subfamily includes several Gab proteins, Drosophila DOS and C. elegans SOC-1. They are scaffolding adaptor proteins, which possess N-terminal PH domains and a C-terminus with proline-rich regions and multiple phosphorylation sites. Following activation of growth factor receptors, Gab proteins are tyrosine phosphorylated and activate PI3K, which generates 3-phosphoinositide lipids. By binding to these lipids via the PH domain, Gab proteins remain in proximity to the receptor, leading to further signaling. While not all Gab proteins depend on the PH domain for recruitment, it is required for Gab activity. Members here include insect, nematodes, and crustacean Gab2s. 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 297303457 525 EGWLWKKKDAKSYFSQKWKKYWFVLKDAS------LYWYINEEDEKAEGFISLPE-------FKIDRASECRKKYAFKAC 591
Cdd:cd13384    6 EGWLTKSPPEKRIWRAKWRRRYFVLRQSEipgqyfLEYYTDRTCRKLKGSIDLDQceqvdagLTFETKNKLKDQHIFDIR 85

                         90       100
                 ....*....|....*....|....
gi 297303457 592 HPKiKSFYFAAEHLDDMNRWLNRI 615
Cdd:cd13384   86 TPK-RTYYLVADTEDEMNKWVNCI 108

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6 pleckstrin homology (PH) domain, C-terminus; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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 297303457 526 GWLWKKKDAKsyfsQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFK---IDRASECRKKYAFKACHPKIKSFYFAA 602
Cdd:cd13237    3 GYLQRRKKSK----KSWKRLWFVLKDKVLYTYKASEDVVALESVPLLGFTvvtIDESFEEDESLVFQLLHKGQLPIIFRA 78

                         90
                 ....*....|...
gi 297303457 603 EHLDDMNRWLNRI 615
Cdd:cd13237   79 DDAETAQRWIEAL 91

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 297303457 523 DCEGWLWKKKDA-KSYfsqkwKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDrASECRKKYAFKACH--PKIKSFY 599
Cdd:cd13288    9 DKEGYLWKKGERnTSY-----QKRWFVLKGNLLFYFEKKGDREPLGVIVLEGCTVE-LAEDAEPYAFAIRFdgPGARSYV 82

                         90
                 ....*....|...
gi 297303457 600 FAAEHLDDMNRWL 612
Cdd:cd13288   83 LAAENQEDMESWM 95

PDZ domain 4 of membrane-associated guanylate kinase inverted 1 (MAGI-1), MAGI-2, and MAGI-3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 4 of MAGI1, 2, 3 (MAGI is also known as Membrane-associated guanylate kinase, WW and PDZ domain-containing protein) and related domains. MAGI proteins have been implicated in the control of cell migration and invasion through altering the activity of phosphatase and tensin homolog (PTEN) and modulating Akt signaling. Four MAGI proteins have been identified (MAGI1-3 and MAGIX). MAGI1-3 have 6 PDZ domains and bind to the C-terminus of PTEN via their PDZ2 domain. MAGIX has a single PDZ domain that is related to MAGI1-3 PDZ domain 5. Other binding partners for MAGI1 include JAM4, C-terminal tail of high risk HPV-18 E6, megalin, TRAF6, Kir4.1 (basolateral K+ channel subunit), and cadherin 23; for MAGI2, include DASM1, dendrin, axin, beta- and delta-catenin, neuroligin, hyperpolarization-activated cation channels, beta1-adrenergic receptors, NMDA receptor, and TARPs; and for MAGI3 includes LPA2. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This MAGI family PDZ4 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2); arranged as beta-strands A, -B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 297303457 222 KPSEGLGMYIKSTYDGL--HVITGTTENSPADRCKKIHAGDEVIQVNHQTV 270
Cdd:cd06734    9 RENEGFGFVIISSVNKKsgSKIGRIIPGSPADRCGQLKVGDRILAVNGISI 59

Fungal proteins Pleckstrin homology (PH) domain, repeat 2; The functions of these fungal proteins are unknown, but they all contain 2 PH domains. This cd represents 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 297303457 524 CEGWLWKKKdAKSYfsQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEF----KIDRASEcRKKYAFKACHPKiKSFY 599
Cdd:cd13299    8 EQGYLQVLK-KKGV--NQWKKYWLVLRNRSLSFYKDQSEYSPVKIIPIDDIidvvELDPLSK-SKKWCLQIITPE-KRIR 82

                         90
                 ....*....|....*....
gi 297303457 600 FAAEHLDDMNRWLNRINML 618
Cdd:cd13299   83 FCADDEESLIKWLGALKSL 101

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 297303457 222 KPSEGLGMYIK--STYDGLHVITGTTENSPADRCKKIHAGDEVIQVNHQTV 270
Cdd:cd00136    7 DPGGGLGFSIRggKDGGGGIFVSRVEPGGPAARDGRLRVGDRILEVNGVSL 57

Rho GTPase activating protein 2 Pleckstrin homology (PH) domain; RhoGAP2 (also called RhoGap22 or ArhGap22) are involved in cell polarity, cell morphology and cytoskeletal organization. They activate a GTPase belonging to the RAS superfamily of small GTP-binding proteins. The encoded protein is insulin-responsive, is dependent on the kinase Akt, and requires the Akt-dependent 14-3-3 binding protein which binds sequentially to two serine residues resulting in regulation of cell motility. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 297303457 526 GWLWKKKDaksyFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISL-----------PE------FKIDRASEcRKKYAF 588
Cdd:cd13378    7 GWLKKQRS----IMKNWQQRWFVLRGDQLFYYKDEEETKPQGCISLqgsqvnelppnPEepgkhlFEILPGGA-GDREKV 81

                         90       100
                 ....*....|....*....|....*..
gi 297303457 589 KACHpkiKSFYFAAEHLDDMNRWLNRI 615
Cdd:cd13378   82 PMNH---EAFLLMANSQSDMEDWVKAI 105

Bruton's tyrosine kinase pleckstrin homology (PH) domain; Btk is a member of the Tec family of cytoplasmic protein tyrosine kinases that includes BMX, IL2-inducible T-cell kinase (Itk) and Tec. Btk plays a role in the maturation of B cells. Tec proteins general have an N-terminal PH domain, followed by a Tek homology (TH) domain, a SH3 domain, a SH2 domain and a kinase domain. The Btk PH domain binds phosphatidylinositol 3,4,5-trisphosphate and responds to signalling via phosphatidylinositol 3-kinase. The PH domain is also involved in membrane anchoring which is confirmed by the discovery of a mutation of a critical arginine residue in the BTK PH domain. This results in severe human immunodeficiency known as X-linked agammaglobulinemia (XLA) in humans and a related disorder is mice.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 297303457 525 EGWLWKKKDAKSYFSQK-WKKYWFVLKDASLYWYINEEDEKAE--GFISLPEFKI----DRASECRKKYAFKACHPKIKS 597
Cdd:cd01238    2 EGLLVKRSQGKKRFGPVnYKERWFVLTKSSLSYYEGDGEKRGKekGSIDLSKVRCveevKDEAFFERKYPFQVVYDDYTL 81

                         90       100
                 ....*....|....*....|....
gi 297303457 598 FYFAAEHLDDmNRWLNRINMLTAG 621
Cdd:cd01238   82 YVFAPSEEDR-DEWIAALRKVCRN 104

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 297303457 541 KWKKYWFVLKDASLYWYINEED--EKAEGFISLPEF-KIDRASECRkkyAFKACHPKiKSFYFAAEHLDDMNRWL 612
Cdd:cd13282   14 TWKRRWFVLKNGELFYYKSPNDviRKPQGQIALDGScEIARAEGAQ---TFEIVTEK-RTYYLTADSENDLDEWI 84

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 297303457 526 GWLWKKKDAksyfSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASE----CRKKYAFKACHPKiKSFYFA 601
Cdd:cd01233   10 GYLLFLEDA----TDGWVRRWVVLRRPYLHIYSSEKDGDERGVINLSTARVEYSPDqealLGRPNVFAVYTPT-NSYLLQ 84

                         90
                 ....*....|....*....
gi 297303457 602 AEHLDDMNRWLNRINMLTA 620
Cdd:cd01233   85 ARSEKEMQDWLYAIDPLLA 103

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 297303457 524 CEGWLWKKKDAKSyfsqKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEF-KIDRASECRKKYAFKACHPKiKSFYFAA 602
Cdd:cd13298    8 KSGYLLKRSRKTK----NWKKRWVVLRPCQLSYYKDEKEYKLRRVINLSELlAVAPLKDKKRKNVFGIYTPS-KNLHFRA 82

                         90
                 ....*....|....*..
gi 297303457 603 EHLDDMNRWLNRINMLT 619
Cdd:cd13298   83 TSEKDANEWVEALREEF 99

Pleckstrin homology (PH) domain containing, family D (with coiled-coil domains) member 1 PH domain; Human PLEKHD1 (also called UPF0639, pleckstrin homology domain containing, family D (with M protein repeats) member 1) is a single transcript and contains a single PH domain. PLEKHD1 is conserved in human, chimpanzee, , dog, cow, mouse, chicken, zebrafish, and Caenorhabditis elegans. 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 297303457 524 CEGWLWKKkdAKSYFSQKWKKYWFVLKDASLYWYinEEDEKAE------------GFISLPEFKIDRASECRKKYAFKAC 591
Cdd:cd13281   14 LHGILWKK--PFGHQSAKWSKRFFIIKEGFLLYY--SESEKKDfektrhfnihpkGVIPLGGCSIEAVEDPGKPYAISIS 89

                         90       100
                 ....*....|....*....|..
gi 297303457 592 HPKIKSFYF-AAEHLDDMNRWL 612
Cdd:cd13281   90 HSDFKGNIIlAADSEFEQEKWL 111

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 297303457 525 EGWLWKKkdakSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPE-FKIDRASECRKKYAFKACHPKiKSFYFAAE 603
Cdd:cd10573    6 EGYLTKL----GGIVKNWKTRWFVLRRNELKYFKTRGDTKPIRVLDLREcSSVQRDYSQGKVNCFCLVFPE-RTFYMYAN 80

                         90
                 ....*....|...
gi 297303457 604 HLDDMNRWLNRIN 616
Cdd:cd10573   81 TEEEADEWVKLLK 93

SAM domain of BOI-like fungal subfamily; SAM (sterile alpha motif) domain of BOI-like fungal subfamily is a potential protein-protein interaction domain. Proteins of this subfamily are apparently scaffold proteins, since most contain SH3 and PH domains, which are also protein-protein interaction domains, in addition to SAM domain. BOI-like proteins participate in cell cycle regulation. In particular BOI1 and BOI2 proteins of budding yeast S.cerevisiae are involved in bud formation, and POB1 protein of fission yeast S.pombe plays a role in cell elongation and separation. Among binding partners of BOI-like fungal subfamily members are such proteins as Bem1 and Cdc42 (they are known to be involved in cell polarization and bud formation).

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 297303457  11 WSPSQVVDWM--KGLDDclqQYIKNFEREKISGDQLLRITHQELEDLGVSRIG 61
Cdd:cd09535    3 WSPEQVAEWLlsAGFDD---SVCEKFRENEITGDILLELDLEDLKELDIGSFG 52