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 569012018  529 SKRRISCKDLGRGDCEGWLWKKKDAKSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRKKYAFK 608
Cdd:cd01260     1 SRRRVSCKDLGRGDCQGWLWKKKEAKSFFGQKWKKYWFVLKGSSLYWYSNQQDEKAEGFINLPDFKIERASECKKKYAFK 80

                          90       100       110
                  ....*....|....*....|....*....|....
gi 569012018  609 ACHPKIKSFYFAAEHLDDMNRWLNRINMLTAGYA 642
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 569012018    84 NLKTLSHKLNASAKNLQNFITGRRRSGHYDGRTSRKLPNDFLTSVVDLIGAAKSLLAWLDRSPFAAVTDYSVTRNNVIQL 163
Cdd:pfam10534    1 NLQSLTEKLRASAHSLQNIIQSRRRSNSYDGRSSVKPPNDVLSAVVELIAAAKGLLSWLDRYPFSQLNDYSATRNNIIQL 80

                           90
                   ....*....|...
gi 569012018   164 CLELTTIVQQDCT 176
Cdd:pfam10534   81 CLELTTTVQKDLT 93

Connector enhancer of kinase suppressor of ras 2/3 domain; This family represents a conserved region of unknown function within Connector enhancer of kinase suppressor of ras 2 (CNK2, also known MAGUIN), Connector enhancer of kinase suppressor of ras 3 (CNK3) and CNK3/IPCEF1 fusion protein. This region is situated between the PDZ pfam00595 and PH pfam00169 domains in CNK2 and CNK3/IPCEF1, and after the PDZ domain in CNK3. All family members also contain an N-terminal pfam00536 domain. CNK2 is predominantly expressed in neural tissues, being critical for postsynaptic density morphology, implicated in X-linked intellectual disability (ID). CNK2 was first described as a regulator of Ras/MAPK signalling that lead to further studies concluding that it act as a scaffold for multiple signal cascades. It is able to direct the localization of regulatory proteins within the cell and influences the behaviour of important regulatory molecules. CNK3 regulates aldosterone-induced and epithelial sodium channel (ENaC)-mediated sodium transport through regulation of ENaC cell surface expression, acting as a scaffold protein that coordinates the assembly of an ENaC-regulatory complex (ERC). CNK3/IPCEF1 is required for hepatocyte growth factor (HGF)-dependent activation of Arf6 and HGF-stimulated cell migration.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569012018   339 TPTKRDSSALQDLYIPPPPAEPYIPRDEKGNLPCEDLRGHMVGKPVHKGSESPNSFLDQEYRKRFNIVEEDTVLYCYEYE 418
Cdd:pfam06663    1 SSKKKEKPAILDLYIPPPPAVPYTPRDEKGSLYSGGSKRPHPGLPGKKGSESPNSFLDQESRRRFTIADYDQLGYGYPYE 80

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 569012018   419 kGRSSSQGRRESTPTY-------------------------------ENSLLRYMSNEK---IAQEEYMFQRN 457
Cdd:pfam06663   81 -ARVPPARRREKTPSYgkprplsmpvdyswvgavdfpakprrggrkgEDLLRRYLSNERippIEEESPSTQPP 152

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 569012018  529 SKRRISCKDLGRGDCEGWLWKKKDAKSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRKKYAFK 608
Cdd:cd01260     1 SRRRVSCKDLGRGDCQGWLWKKKEAKSFFGQKWKKYWFVLKGSSLYWYSNQQDEKAEGFINLPDFKIERASECKKKYAFK 80

                          90       100       110
                  ....*....|....*....|....*....|....
gi 569012018  609 ACHPKIKSFYFAAEHLDDMNRWLNRINMLTAGYA 642
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 569012018    84 NLKTLSHKLNASAKNLQNFITGRRRSGHYDGRTSRKLPNDFLTSVVDLIGAAKSLLAWLDRSPFAAVTDYSVTRNNVIQL 163
Cdd:pfam10534    1 NLQSLTEKLRASAHSLQNIIQSRRRSNSYDGRSSVKPPNDVLSAVVELIAAAKGLLSWLDRYPFSQLNDYSATRNNIIQL 80

                           90
                   ....*....|...
gi 569012018   164 CLELTTIVQQDCT 176
Cdd:pfam10534   81 CLELTTTVQKDLT 93

Connector enhancer of kinase suppressor of ras 2/3 domain; This family represents a conserved region of unknown function within Connector enhancer of kinase suppressor of ras 2 (CNK2, also known MAGUIN), Connector enhancer of kinase suppressor of ras 3 (CNK3) and CNK3/IPCEF1 fusion protein. This region is situated between the PDZ pfam00595 and PH pfam00169 domains in CNK2 and CNK3/IPCEF1, and after the PDZ domain in CNK3. All family members also contain an N-terminal pfam00536 domain. CNK2 is predominantly expressed in neural tissues, being critical for postsynaptic density morphology, implicated in X-linked intellectual disability (ID). CNK2 was first described as a regulator of Ras/MAPK signalling that lead to further studies concluding that it act as a scaffold for multiple signal cascades. It is able to direct the localization of regulatory proteins within the cell and influences the behaviour of important regulatory molecules. CNK3 regulates aldosterone-induced and epithelial sodium channel (ENaC)-mediated sodium transport through regulation of ENaC cell surface expression, acting as a scaffold protein that coordinates the assembly of an ENaC-regulatory complex (ERC). CNK3/IPCEF1 is required for hepatocyte growth factor (HGF)-dependent activation of Arf6 and HGF-stimulated cell migration.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569012018   339 TPTKRDSSALQDLYIPPPPAEPYIPRDEKGNLPCEDLRGHMVGKPVHKGSESPNSFLDQEYRKRFNIVEEDTVLYCYEYE 418
Cdd:pfam06663    1 SSKKKEKPAILDLYIPPPPAVPYTPRDEKGSLYSGGSKRPHPGLPGKKGSESPNSFLDQESRRRFTIADYDQLGYGYPYE 80

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 569012018   419 kGRSSSQGRRESTPTY-------------------------------ENSLLRYMSNEK---IAQEEYMFQRN 457
Cdd:pfam06663   81 -ARVPPARRREKTPSYgkprplsmpvdyswvgavdfpakprrggrkgEDLLRRYLSNERippIEEESPSTQPP 152

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 569012018     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 569012018   543 CEGWLWKKKdakSYFSQKWKKYWFVLKDASLYWY---INEEDEKAEGFISLPEFKIDRASECR---KKYAFKACHPKI-- 614
Cdd:pfam00169    3 KEGWLLKKG---GGKKKSWKKRYFVLFDGSLLYYkddKSGKSKEPKGSISLSGCEVVEVVASDspkRKFCFELRTGERtg 79

                           90       100
                   ....*....|....*....|....*.
gi 569012018   615 -KSFYFAAEHLDDMNRWLNRINMLTA 639
Cdd:pfam00169   80 kRTYLLQAESEEERKDWIKAIQSAIR 105

PDZ domain; PDZ domains are found in diverse signaling proteins.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 569012018   225 EGLGMYIKSTYDGLH---VITGTTENSPADRcKKIHAGDEVIQVNHQTVVGWQLKNLVNALRedPSGVILTLK 294
Cdd:pfam00595   10 GGLGFSLKGGSDQGDpgiFVSEVLPGGAAEA-GGLKVGDRILSINGQDVENMTHEEAVLALK--GSGGKVTLT 79

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 569012018  529 SKRRISCKDLGRGDCEGWLWKKKDAKSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRKKYAFK 608
Cdd:cd01260     1 SRRRVSCKDLGRGDCQGWLWKKKEAKSFFGQKWKKYWFVLKGSSLYWYSNQQDEKAEGFINLPDFKIERASECKKKYAFK 80

                          90       100       110
                  ....*....|....*....|....*....|....
gi 569012018  609 ACHPKIKSFYFAAEHLDDMNRWLNRINMLTAGYA 642
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 569012018    84 NLKTLSHKLNASAKNLQNFITGRRRSGHYDGRTSRKLPNDFLTSVVDLIGAAKSLLAWLDRSPFAAVTDYSVTRNNVIQL 163
Cdd:pfam10534    1 NLQSLTEKLRASAHSLQNIIQSRRRSNSYDGRSSVKPPNDVLSAVVELIAAAKGLLSWLDRYPFSQLNDYSATRNNIIQL 80

                           90
                   ....*....|...
gi 569012018   164 CLELTTIVQQDCT 176
Cdd:pfam10534   81 CLELTTTVQKDLT 93

Connector enhancer of kinase suppressor of ras 2/3 domain; This family represents a conserved region of unknown function within Connector enhancer of kinase suppressor of ras 2 (CNK2, also known MAGUIN), Connector enhancer of kinase suppressor of ras 3 (CNK3) and CNK3/IPCEF1 fusion protein. This region is situated between the PDZ pfam00595 and PH pfam00169 domains in CNK2 and CNK3/IPCEF1, and after the PDZ domain in CNK3. All family members also contain an N-terminal pfam00536 domain. CNK2 is predominantly expressed in neural tissues, being critical for postsynaptic density morphology, implicated in X-linked intellectual disability (ID). CNK2 was first described as a regulator of Ras/MAPK signalling that lead to further studies concluding that it act as a scaffold for multiple signal cascades. It is able to direct the localization of regulatory proteins within the cell and influences the behaviour of important regulatory molecules. CNK3 regulates aldosterone-induced and epithelial sodium channel (ENaC)-mediated sodium transport through regulation of ENaC cell surface expression, acting as a scaffold protein that coordinates the assembly of an ENaC-regulatory complex (ERC). CNK3/IPCEF1 is required for hepatocyte growth factor (HGF)-dependent activation of Arf6 and HGF-stimulated cell migration.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569012018   339 TPTKRDSSALQDLYIPPPPAEPYIPRDEKGNLPCEDLRGHMVGKPVHKGSESPNSFLDQEYRKRFNIVEEDTVLYCYEYE 418
Cdd:pfam06663    1 SSKKKEKPAILDLYIPPPPAVPYTPRDEKGSLYSGGSKRPHPGLPGKKGSESPNSFLDQESRRRFTIADYDQLGYGYPYE 80

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 569012018   419 kGRSSSQGRRESTPTY-------------------------------ENSLLRYMSNEK---IAQEEYMFQRN 457
Cdd:pfam06663   81 -ARVPPARRREKTPSYgkprplsmpvdyswvgavdfpakprrggrkgEDLLRRYLSNERippIEEESPSTQPP 152

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 569012018  542 DCEGWLWKKkdAKSYFSQkWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRAS---ECRKKYAFKACHPKIKSFY 618
Cdd:cd13248     8 VMSGWLHKQ--GGSGLKN-WRKRWFVLKDNCLYYYKDPEEEKALGSILLPSYTISPAPpsdEISRKFAFKAEHANMRTYY 84

                          90
                  ....*....|....*..
gi 569012018  619 FAAEHLDDMNRWLNRIN 635
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 569012018     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 569012018  542 DCEGWLWKKKDAKSyfsqKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRK---KYAFKACHPKI-KSF 617
Cdd:cd13316     1 DHSGWMKKRGERYG----TWKTRYFVLKGTRLYYLKSENDDKEKGLIDLTGHRVVPDDSNSPfrgSYGFKLVPPAVpKVH 76

                          90
                  ....*....|....*
gi 569012018  618 YFAAEHLDDMNRWLN 632
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 569012018   15 QVVDWMKGLDdcLQQYIKNFEREKISGDQLLRITHQELEDLGVSRIGHQELILEAVD 71
Cdd:cd09487     1 DVAEWLESLG--LEQYADLFRKNEIDGDALLLLTDEDLKELGITSPGHRKKILRAIQ 55

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        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 569012018  222 KPSEGLGMYIK--STYDGLHVITGTTENSPADRCKKIHAGDEVIQVNHQTVVGWQLKNLVNALREDPSGVILTLK 294
Cdd:cd00136     7 DPGGGLGFSIRggKDGGGGIFVSRVEPGGPAARDGRLRVGDRILEVNGVSLEGLTHEEAVELLKSAGGEVTLTVR 81

SH3 domain-binding protein 2 Pleckstrin homology (PH) domain; SH3BP2 (the gene that encodes the adaptor protein 3BP2), HD, ITU, IT10C3, and ADD1 are located near the Huntington's Disease Gene on Human Chromosome 4pl6.3. SH3BP2 lies in a region that is often missing in individuals with Wolf-Hirschhorn syndrome (WHS). Gain of function mutations in SH3BP2 causes enhanced B-cell antigen receptor (BCR)-mediated activation of nuclear factor of activated T cells (NFAT), resulting in a rare, genetic disorder called cherubism. This results in an increase in the signaling complex formation with Syk, phospholipase C-gamma2 (PLC-gamma2), and Vav1. It was recently discovered that Tankyrase regulates 3BP2 stability through ADP-ribosylation and ubiquitylation by the E3-ubiquitin ligase. Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the Src, Syk, and Vav signaling pathways. SH3BP2 is also a potential negative regulator of the abl oncogene. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569012018  537 DLGRGDC--EGWLwKKKDAKSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECR--KKYAFKACH- 611
Cdd:cd13308     3 LTLPRDVihSGTL-TKKGGSQKTLQNWQLRYVIIHQGCVYYYKNDQSAKPKGVFSLNGYNRRAAEERTskLKFVFKIIHl 81

                          90       100
                  ....*....|....*....|....*
gi 569012018  612 -PKIKSFYFAAEHLDDMNRWLNRIN 635
Cdd:cd13308    82 sPDHRTWYFAAKSEDEMSEWMEYIR 106

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 569012018  544 EGWLWKKKDAKSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRKK----YAFKACHPKIKSFYF 619
Cdd:cd13266     4 AGYLEKRRKDHSFFGSEWQKRWCAISKNVFYYYGSDKDKQQKGEFAINGYDVRMNPTLRKDgkkdCCFELVCPDKRTYQF 83

                          90
                  ....*....|....*...
gi 569012018  620 AAEHLDDMNRWLNRINML 637
Cdd:cd13266    84 TAASPEDAEDWVDQISFI 101

SAM domain of Ste50_like (ubc2) subfamily; SAM (sterile alpha motif) domain of Ste50-like (or Ubc2 for Ustilago bypass of cyclase) subfamily is a putative protein-protein interaction domain. This group includes only fungal proteins. Basidiomycetes have an N-terminal SAM domain, central UBQ domain, and C-terminal SH3 domain, while Ascomycetes lack the SH3 domain. Ubc2 of Ustilago maydis is a major virulence and maize pathogenicity factor. It is required for filamentous growth (the budding haploid form of Ustilago maydis is a saprophyte, while filamentous dikaryotic form is a pathogen). Also the Ubc2 protein is involved in the pheromone-responsive morphogenesis via the MAP kinase cascade. The SAM domain is necessary for ubc2 function; deletion of SAM eliminates this function. A Lys-to-Glu mutation in the SAM domain of ubc2 gene induces temperature sensitivity.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 569012018   15 QVVDWMKGLDdcLQQYIKNFEREKISGDQLLRITHQELEDLGVSRIGHQELILEAV 70
Cdd:cd09533     1 DVADWLSSLG--LPQYEDQFIENGITGDVLVALDHEDLKEMGITSVGHRLTILKAV 54

SAM domain of diacylglycerol kinase delta and eta subunits; SAM (sterile alpha motif) domain of DGK-eta-delta subfamily proteins is a protein-protein interaction domain. Proteins of this subfamily are multidomain diacylglycerol kinases with a SAM domain located at the C-terminus. DGK proteins participate in signal transduction. They regulate the level of second messengers such as diacylglycerol and phosphatidic acid. The SAM domain of DGK proteins can form high molecular weight homooligomers through head-to-tail interactions as well as heterooligomers between the SAM domains of DGK delta and eta proteins. The oligomerization plays a role in the regulation of DGK intracellular localization.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 569012018    7 PVSKWSPSQVVDWMKGLDdcLQQYIKNFEREKISGDQLLRITHQELEDLGVSRIGHQELILEAV 70
Cdd:cd09507     1 PVTNWTTEEVGAWLESLQ--LGEYRDIFARNDIRGSELLHLERRDLKDLGITKVGHVKRILQAI 62

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 569012018  543 CEGWLWKKKDAKSYFSQKWKKYWFVLKDAS-------LYWYINEEDEKAEGFISLPEFKIDRAS------ECRKKYAFKA 609
Cdd:cd13324     3 YEGWLTKSPPEKKIWRAAWRRRWFVLRSGRlsggqdvLEYYTDDHCKKLKGIIDLDQCEQVDAGltfekkKFKNQFIFDI 82

                          90       100
                  ....*....|....*....|....*
gi 569012018  610 CHPKiKSFYFAAEHLDDMNRWLNRI 634
Cdd:cd13324    83 RTPK-RTYYLVAETEEEMNKWVRCI 106

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 569012018  545 GWLWKKKDAKSYFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASECRKKY----AFKACHPKIKSFYFA 620
Cdd:cd13381     5 GYLEKRRKDHSFFGFEWQKRWCALSNSVFYYYGSDKDKQQKGEFAIDGYDVKMNNTLRKDAkkdcCFEICAPDKRVYQFT 84

                          90
                  ....*....|....*..
gi 569012018  621 AEHLDDMNRWLNRINML 637
Cdd:cd13381    85 AASPKEAEEWVQQIKFI 101

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 569012018  544 EGWLWKKKDAKSYFSQKWKKYWFVLKDAS------LYWYINEEDEKAEGFISLPE-------FKIDRASECRKKYAFKAC 610
Cdd:cd13384     6 EGWLTKSPPEKRIWRAKWRRRYFVLRQSEipgqyfLEYYTDRTCRKLKGSIDLDQceqvdagLTFETKNKLKDQHIFDIR 85

                          90       100
                  ....*....|....*....|....
gi 569012018  611 HPKiKSFYFAAEHLDDMNRWLNRI 634
Cdd:cd13384    86 TPK-RTYYLVADTEDEMNKWVNCI 108

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569012018    214 EVIQLANIKPSEGLGMYIKSTYDGLH--VITGTTENSPADRCKkIHAGDEVIQVNHQTVVGWQLKNLVNALREDPSGVIL 291
Cdd:smart00228    1 EPRLVELEKGGGGLGFSLVGGKDEGGgvVVSSVVPGSPAAKAG-LRVGDVILEVNGTSVEGLTHLEAVDLLKKAGGKVTL 79

                    ....*.
gi 569012018    292 TLKKRP 297
Cdd:smart00228   80 TVLRGG 85

PDZ domain 4 of multi-PDZ-domain protein 1 (MUPP1) and PATJ (protein-associated tight junction) and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 4 of MUPP1 and PATJ, and related domains. MUPP1 and PATJ serve as scaffolding proteins linking different proteins and protein complexes involved in the organization of tight junctions and epithelial polarity. MUPP1 contains an L27 (Lin-2 and Lin-7 binding) domain and 13 PDZ domains. PATJ (also known as INAD-like) contains an L27 domain and ten PDZ domains. MUPP1 and PATJ share several binding partners, including junctional adhesion molecules (JAM), zonula occludens (ZO)-3, Pals1 (protein associated with Lin-7), Par (partitioning defective)-6 proteins, and nectins (adherence junction adhesion molecules). PATJ lacks 3 PDZ domains seen in MUPP1: PDZ6, 9, and 13; consequently, MUPP1 PDZ7 and 8 align with PATJ PDZ6 and 7; and MUPP1 PDZ domains 10-12 align with PATJ PDZ domains 8-10. 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 MUPP1-like family PDZ4 domain is a canonical PDZ domain containing 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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569012018  214 EVIQLANIKPSEGLGMYIKSTYD----GLHVITGTTENSPADRCKKIHAGDEVIQVNHQTVVGWQLKNLVNALREDPSGV 289
Cdd:cd06668     3 VVAQLSKFSESSGLGISLEGTVDvevrGHHYIRSILPEGPVGRNGKLFSGDELLEVNGIQLLGLSHKEVVSILKELPPPV 82

                  ..
gi 569012018  290 IL 291
Cdd:cd06668    83 RL 84

SAM domain of diacylglycerol kinase eta; SAM (sterile alpha motif) domain of DGK-eta subfamily proteins is a protein-protein interaction domain. Proteins of this subfamily are multidomain diacylglycerol kinases. The SAM domain is located at the C-terminus of two out of three isoforms of DGK-eta protein. DGK-eta proteins participate in signal transduction. They regulate the level of second messengers such as diacylglycerol and phosphatidic acid. The SAM domain of DCK-eta proteins can form high molecular weight homooligomers through head-to-tail interactions as well as heterooligomers with the SAM domain of DGK-delta proteins. The oligomerization plays a role in the regulation of the DGK-delta intracellular localization: it is responsible for sustained endosomal localization of the protein and resulted in negative regulation of DCK-eta catalytic activity.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 569012018    7 PVSKWSPSQVVDWMKGLDdcLQQYIKNFEREKISGDQLLRITHQELEDLGVSRIGHQELILEAVDLL 73
Cdd:cd09576     1 PVQKWGTDEVAAWLDLLS--LGEYKEIFIRHDIRGSELLHLERRDLKDLGIPKVGHMKRILQGIKEL 65

Tandem PH-domain-containing protein 2 Pleckstrin homology (PH) domain; The binding of TAPP2 (also called PLEKHA2) adaptors to PtdIns(3,4)P(2), but not PI(3,4, 5)P3, function as negative regulators of insulin and PI3K signalling pathways (i.e. TAPP/utrophin/syntrophin complex). TAPP2 contains two sequential PH domains in which the C-terminal PH domain specifically binds PtdIns(3,4)P2 with high affinity. The N-terminal PH domain does not interact with any phosphoinositide tested. They also contain a C-terminal PDZ-binding motif that interacts with several PDZ-binding proteins, including PTPN13 (known previously as PTPL1 or FAP-1) as well as the scaffolding proteins MUPP1 (multiple PDZ-domain-containing protein 1), syntrophin and utrophin. The members here are most sequence similar to TAPP2 proteins, but may not be actual TAPP2 proteins. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569012018  545 GWLWKKKDAKsyfsQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEfkIDRASEC---RKKYAFKACHPKiKSFYFAA 621
Cdd:cd13255    10 GYLEKKGERR----KTWKKRWFVLRPTKLAYYKNDKEYRLLRLIDLTD--IHTCTEVqlkKHDNTFGIVTPA-RTFYVQA 82

                          90       100
                  ....*....|....*....|....*...
gi 569012018  622 EHLDDMNRWLNRINMLTAGYAERERIKQ 649
Cdd:cd13255    83 DSKAEMESWISAINLARQALRATITPNT 110

Rho GTPase activating protein 25 and related proteins Pleckstrin homology (PH) domain; RhoGAP25 (also called ArhGap25) like other RhoGaps are involved in cell polarity, cell morphology and cytoskeletal organization. They act as GTPase activators for the Rac-type GTPases by converting them to an inactive GDP-bound state and control actin remodeling by inactivating Rac downstream of Rho leading to suppress leading edge protrusion and promotes cell retraction to achieve cellular polarity and are able to suppress RAC1 and CDC42 activity in vitro. Overexpression of these proteins induces cell rounding with partial or complete disruption of actin stress fibers and formation of membrane ruffles, lamellipodia, and filopodia. This hierarchy contains RhoGAP22, RhoGAP24, and RhoGAP25. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 569012018  545 GWLWKKKDaksyFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLP 591
Cdd:cd13263     7 GWLKKQGS----IVKNWQQRWFVLRGDQLYYYKDEDDTKPQGTIPLP 49

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 569012018  545 GWLWKKKDaksyFSQKWKKYWFVLKDASLYWYINEEDEKAEGFISL-----------PE------FKIDRASEcRKKYAF 607
Cdd:cd13378     7 GWLKKQRS----IMKNWQQRWFVLRGDQLFYYKDEEETKPQGCISLqgsqvnelppnPEepgkhlFEILPGGA-GDREKV 81

                          90       100
                  ....*....|....*....|....*..
gi 569012018  608 KACHpkiKSFYFAAEHLDDMNRWLNRI 634
Cdd:cd13378    82 PMNH---EAFLLMANSQSDMEDWVKAI 105

SAM domain of TAL subfamily; SAM (sterile alpha motif) domain of TAL (Tsg101-associated ligase) proteins, also known as LRSAM1 (Leucine-rich repeat and sterile alpha motif-containing) proteins, is a putative protein-protein interaction domain. Proteins of this subfamily participate in the regulation of retrovirus budding and receptor endocytosis. They show E3 ubiquitin ligase activity. Human TAL protein interacts with Tsg101 and TAL's C-terminal ring finger domain is essential for the multiple monoubiquitylation of Tsg101.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 569012018   15 QVVDWMKGLDdcLQQYIKNFEREKISGDQLLRITHQELEDLGVSRIGHQELILEAVDLL 73
Cdd:cd09523     7 QLVNLLNELS--AEHYLPVFARHRITMETLSTMTDEDLKKIGIHEIGLRKEILRAAQEL 63

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 569012018  544 EGWLWKKKDaksyFSQKWKKYWFVLKDASLYWYINEE---DEKAEGFISLPEFKIDRASE--CRKKYAFKACHPKiKSFY 618
Cdd:cd13276     2 AGWLEKQGE----FIKTWRRRWFVLKQGKLFWFKEPDvtpYSKPRGVIDLSKCLTVKSAEdaTNKENAFELSTPE-ETFY 76

                          90
                  ....*....|....*.
gi 569012018  619 FAAEHLDDMNRWLNRI 634
Cdd:cd13276    77 FIADNEKEKEEWIGAI 92

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 569012018  545 GWLWKKKDAksyfSQKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEFKIDRASE----CRKKYAFKACHPKiKSFYFA 620
Cdd:cd01233    10 GYLLFLEDA----TDGWVRRWVVLRRPYLHIYSSEKDGDERGVINLSTARVEYSPDqealLGRPNVFAVYTPT-NSYLLQ 84

                          90
                  ....*....|....*....
gi 569012018  621 AEHLDDMNRWLNRINMLTA 639
Cdd:cd01233    85 ARSEKEMQDWLYAIDPLLA 103

Amyloid beta (A4) Precursor protein-Binding, family B, member 1 Interacting Protein pleckstrin homology (PH) domain; APBB1IP consists of a Ras-associated (RA) domain, a PH domain, a family-specific BPS region, and a C-terminal SH2 domain. Grb7, Grb10 and Grb14 are paralogs that are also present in this hierarchy. These adapter proteins bind a variety of receptor tyrosine kinases, including the insulin and insulin-like growth factor-1 (IGF1) receptors. Grb10 and Grb14 are important tissue-specific negative regulators of insulin and IGF1 signaling based and may contribute to type 2 (non-insulin-dependent) diabetes in humans. RA-PH function as a single structural unit and is dimerized via a helical extension of the PH domain. The PH domain here are proposed to bind phosphoinositides non-cannonically ahd are unlikely to bind an activated GTPase. The tandem RA-PH domains are present in a second adapter-protein family, MRL proteins, Caenorhabditis elegans protein MIG-1012, the mammalian proteins RIAM and lamellipodin and the Drosophila melanogaster protein Pico12, all of which are Ena/VASP-binding proteins involved in actin-cytoskeleton rearrangement. 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 569012018  544 EGWLWKKKDAKsyfsQKWKKYWFVLKDASLYWYINEEDEKAEG---FISLPEFKIDRASECRKKY--------AFKacHP 612
Cdd:cd01259     9 EGFLYLKEDGK----KSWKKRYFVLRASGLYYSPKGKSKESRDlqcLAQFDDYNVYTGLNGKKKYkaptdfgfCLK--PN 82

                          90       100       110
                  ....*....|....*....|....*....|....
gi 569012018  613 KIKSF------YFAAEHLDDMNRWLNRINMLTAG 640
Cdd:cd01259    83 KQQEKgskdikYLCAEDEQSRTCWLTAIRLAKYG 116

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 569012018  543 CEGWLWKKKDAKSyfsqKWKKYWFVLKDASLYWYINEEDEKAEGFISLPEF-KIDRASECRKKYAFKACHPKiKSFYFAA 621
Cdd:cd13298     8 KSGYLLKRSRKTK----NWKKRWVVLRPCQLSYYKDEKEYKLRRVINLSELlAVAPLKDKKRKNVFGIYTPS-KNLHFRA 82