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 167522130  897 KRGVLWKKAQGTSLLGRDNFKRRTFILTDTCLSYYSGVDISEMKQKGQIPLTKIRAVEVAHATP-WGRSNMIQVVHDDAI 975
Cdd:cd01238     1 LEGLLVKRSQGKKRFGPVNYKERWFVLTKSSLSYYEGDGEKRGKEKGSIDLSKVRCVEEVKDEAfFERKYPFQVVYDDYT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 167522130  976 LYVDAESQAERQDWideIRSACQEGQNVSSKHYNYHPGVFHKGEWTCCATKEQ-GGGCKPAF 1036
Cdd:cd01238    81 LYVFAPSEEDRDEW---IAALRKVCRNNSNLHDKYHPGFWTGGKWSCCGQTSKsAPGCQPAF 139

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 167522130  897 KRGVLWKKAQGTSLLGRDNFKRRTFILTDTCLSYYSGVDISEMKQKGQIPLTKIRAVEVAHATP-WGRSNMIQVVHDDAI 975
Cdd:cd01238     1 LEGLLVKRSQGKKRFGPVNYKERWFVLTKSSLSYYEGDGEKRGKEKGSIDLSKVRCVEEVKDEAfFERKYPFQVVYDDYT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 167522130  976 LYVDAESQAERQDWideIRSACQEGQNVSSKHYNYHPGVFHKGEWTCCATKEQ-GGGCKPAF 1036
Cdd:cd01238    81 LYVFAPSEEDRDEW---IAALRKVCRNNSNLHDKYHPGFWTGGKWSCCGQTSKsAPGCQPAF 139

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130   897 KRGVLWKKAQGtsllGRDNFKRRTFILTDTCLSYYSGVDISEMKQ-KGQIPLTKIRAVEVAHATPWGRSNMIQVVHDDAI 975
Cdd:pfam00169    3 KEGWLLKKGGG----KKKSWKKRYFVLFDGSLLYYKDDKSGKSKEpKGSISLSGCEVVEVVASDSPKRKFCFELRTGERT 78

                           90       100
                   ....*....|....*....|....*.
gi 167522130   976 ----LYVDAESQAERQDWIDEIRSAC 997
Cdd:pfam00169   79 gkrtYLLQAESEEERKDWIKAIQSAI 104

Alpha helical coiled-coil rod protein (HCR); This family consists of several mammalian alpha helical coiled-coil rod HCR proteins. The function of HCR is unknown but it has been implicated in psoriasis in humans and is thought to affect keratinocyte proliferation.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130   486 SSPMASVSQPVALDMQNGLQH------------TATAELIQHIKSILLEDPRLDLENKFDVLQQLQSYVFTLEERLAAQQ 553
Cdd:pfam07111  465 SCPPPPPAPPVDADLSLELEQlreernrldaelQLSAHLIQQEVGRAREQGEAERQQLSEVAQQLEQELQRAQESLASVG 544

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130   554 QrnlELETALSNTQEQLQKRQSTLAMLDKQRTNNQSALLEMINDFHADFVEKLDRHERRFGEARttldtihSDVERQMVT 633
Cdd:pfam07111  545 Q---QLEVARQGQQESTEEAASLRQELTQQQEIYGQALQEKVAEVETRLREQLSDTKRRLNEAR-------REQAKAVVS 614

                          170       180       190
                   ....*....|....*....|....*....|.
gi 167522130   634 MRDIQTRA------NDFLQELQMKAEHLETE 658
Cdd:pfam07111  615 LRQIQHRAtqekerNQELRRLQDEARKEEGQ 645

Predicted nucleic acid-binding protein DR0291, contains C4-type Zn-ribbon domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130  535 LQQLQSYVFTLEERLAAQQQRNLELETALSNTQEQLQKRQSTLAMLDKQRTNNQSALlemindfhADFVEKLDRHERRFG 614
Cdd:COG1579    12 LQELDSELDRLEHRLKELPAELAELEDELAALEARLEAAKTELEDLEKEIKRLELEI--------EEVEARIKKYEEQLG 83

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 167522130  615 EARTTLDtiHSDVERQMVTMRDIQTRANDFLQELQMKAEHLETELS 660
Cdd:COG1579    84 NVRNNKE--YEALQKEIESLKRRISDLEDEILELMERIEELEEELA 127

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 167522130  897 KRGVLWKKAQGTSLLGRDNFKRRTFILTDTCLSYYSGVDISEMKQKGQIPLTKIRAVEVAHATP-WGRSNMIQVVHDDAI 975
Cdd:cd01238     1 LEGLLVKRSQGKKRFGPVNYKERWFVLTKSSLSYYEGDGEKRGKEKGSIDLSKVRCVEEVKDEAfFERKYPFQVVYDDYT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 167522130  976 LYVDAESQAERQDWideIRSACQEGQNVSSKHYNYHPGVFHKGEWTCCATKEQ-GGGCKPAF 1036
Cdd:cd01238    81 LYVFAPSEEDRDEW---IAALRKVCRNNSNLHDKYHPGFWTGGKWSCCGQTSKsAPGCQPAF 139

GTPase activating protein 1 m pleckstrin homology (PH) domain; GAP1(m) (also called RASA2/RAS p21 protein activator (GTPase activating protein) 2) is a member of the GAP1 family of GTPase-activating proteins, along with RASAL1, GAP1(IP4BP), and CAPRI. With the notable exception of GAP1(m), they all possess an arginine finger-dependent GAP activity on the Ras-related protein Rap1. GAP1(m) contains two C2 domains, a PH domain, a RasGAP domain, and a BTK domain. Its C2 domains, like those of GAP1IP4BP, do not contain the C2 motif that is known to be required for calcium-dependent phospholipid binding. GAP1(m) is regulated by the binding of its PH domains to phophoinositides, PIP3 (phosphatidylinositol 3,4,5-trisphosphate). It suppresses RAS, enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, allowing control of cellular proliferation and differentiation. GAP1(m) binds inositol tetrakisphosphate (IP4). 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 167522130  897 KRGVLWKKAQGTSLLGRDNFKRRTFILTDTCLSYYsgvdisemKQKGQ-----IPLTKIRAVEVAHATPWGRSNMIQVVH 971
Cdd:cd13370    18 KEGEMHKRAQGRTRIGKKNFKKRWFCLTSRELTYH--------KQKGKeaiftIPVKNILAVEKLEESAFNKKNMFQVIH 89

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 167522130  972 DDAILYVDAESQAERQDWIDEIRSACQEGQNVSSKhynYHPGVFHKG 1018
Cdd:cd13370    90 SEKPLYVQANNCVEANEWIEVLSRVSRCNQKRLSF---YHPSAYLGG 133

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130  897 KRGVLWKKaqgtSLLGRDNFKRRTFILTDTCLSYYSGVDISEMKQKGQIPLTKIraVEVAHATPWGRSNMIQVVH-DDAI 975
Cdd:cd00821     1 KEGYLLKR----GGGGLKSWKKRWFVLFEGVLLYYKSKKDSSYKPKGSIPLSGI--LEVEEVSPKERPHCFELVTpDGRT 74

                          90
                  ....*....|....*...
gi 167522130  976 LYVDAESQAERQDWIDEI 993
Cdd:cd00821    75 YYLQADSEEERQEWLKAL 92

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130   897 KRGVLWKKAQGtsllGRDNFKRRTFILTDTCLSYYSGVDISEMKQ-KGQIPLTKIRAVEVAHATPWGRSNMIQVVHDDAI 975
Cdd:pfam00169    3 KEGWLLKKGGG----KKKSWKKRYFVLFDGSLLYYKDDKSGKSKEpKGSISLSGCEVVEVVASDSPKRKFCFELRTGERT 78

                           90       100
                   ....*....|....*....|....*.
gi 167522130   976 ----LYVDAESQAERQDWIDEIRSAC 997
Cdd:pfam00169   79 gkrtYLLQAESEEERKDWIKAIQSAI 104

Ras-GTPase-activating-like protein pleckstrin homology (PH) domain; RASAL1 is a member of the GAP1 family of GTPase-activating proteins, along with GAP1(m), GAP1(IP4BP) and CAPRI. RASAL1 contains two C2 domains, a PH domain, a RasGAP domain, and a BTK domain. RASAL1 contains two fully conserved C2 domains, a PH domain, a RasGAP domain, and a BTK domain. Its catalytic GAP domain has dual RasGAP and RapGAP activities, while its C2 domains bind phospholipids in the presence of Ca2+. Both CAPRI and RASAL1 are calcium-activated RasGAPs that inactivate Ras at the plasma membrane. Thereby enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS and allowing control of cellular proliferation and differentiation. CAPRI and RASAL1 differ in that CAPRI is an amplitude sensor while RASAL1 senses calcium oscillations. This difference between them resides not in their C2 domains, but in their PH domains leading to speculation that this might reflect an association with either phosphoinositides and/or 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 167522130  897 KRGVLWK-KAQGTSLLGRDNFKRRTFILTDTCLSYYSGvdiSEMKQKGQIPLTKIRAVEVAHATPWGRSNMIQVVHDDA- 974
Cdd:cd13369    17 KEGYLHKrKAEGVGLVTRFTFKKRYFWLSSETLSYSKS---PDWQVRSSIPVQRICAVERVDENAFQQPNVMQVVTQDGe 93

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 167522130  975 ----ILYVDAESQAERQDWIDEIRSACQEGQNVSSkhyNYHPGVFHKG 1018
Cdd:cd13369    94 gqvhTTYIQCKNVNELNQWLSALRKVSLSNERMLP---ACHPGAFRSA 138

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 167522130  897 KRGVLWKKAQGTSllgrdNFKRRTFILTDTCLSYYSgvDISEMKQKGQIPLTKIRAV---EVAHatpwgRSNMIQVVHDD 973
Cdd:cd13298     8 KSGYLLKRSRKTK-----NWKKRWVVLRPCQLSYYK--DEKEYKLRRVINLSELLAVaplKDKK-----RKNVFGIYTPS 75

                          90       100
                  ....*....|....*....|..
gi 167522130  974 AILYVDAESQAERQDWIDEIRS 995
Cdd:cd13298    76 KNLHFRATSEKDANEWVEALRE 97

Ca2+ promoted Ras inactivator pleckstrin homology (PH) domain; CAPRI (also called RASA4/RAS p21 protein activator (GTPase activating protein) 4/GAPL/FLJ59070/KIAA0538/MGC131890) is a member of the GAP1 family of GTPase-activating proteins. CAPRI contains two fully conserved C2 domains, a PH domain, a RasGAP domain, and a BTK domain. Its catalytic GAP domain has dual RasGAP and RapGAP activities, while its C2 domains bind phospholipids in the presence of Ca2+. Both CAPRI and RASAL are calcium-activated RasGAPs that inactivate Ras at the plasma membrane. Thereby enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS and allowing control of cellular proliferation and differentiation. CAPRI and RASAL differ in that CAPRI is an amplitude sensor while RASAL senses calcium oscillations. This difference between them resides not in their C2 domains, but in their PH domains leading to speculation that this might reflect an association with either phosphoinositides and/or 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 167522130  897 KRGVLW-KKAQGTSLLGRDNFKRRTFILTDTCLSYysgVDISEMKQKGQIPLTKIRAVEVAHATPWGRSNMIQVVH-DDA 974
Cdd:cd13372    28 KEGFLFiHRTKGKGPLMASSFKKLYFTLTKDALSF---AKTPHSKKSSSISLAKIRAAEKVEEKCFGSSNVMQIIYtDDA 104

                          90       100
                  ....*....|....*....|....*..
gi 167522130  975 ----ILYVDAESQAERQDWIDEIRSAC 997
Cdd:cd13372   105 gqqeTLYLQCKSVNELNQWLSALRKVC 131

General Receptor for Phosphoinositides-1-like Pleckstrin homology (PH) domain; GRP1/cytohesin3 and the related proteins ARNO (ARF nucleotide-binding site opener)/cytohesin-2 and cytohesin-1 are ARF exchange factors that contain a pleckstrin homology (PH) domain thought to target these proteins to cell membranes through binding polyphosphoinositides. The PH domains of all three proteins exhibit relatively high affinity for PtdIns(3,4,5)P3. Within the Grp1 family, diglycine (2G) and triglycine (3G) splice variants, differing only in the number of glycine residues in the PH domain, strongly influence the affinity and specificity for phosphoinositides. The 2G variants selectively bind PtdIns(3,4,5)P3 with high affinity,the 3G variants bind PtdIns(3,4,5)P3 with about 30-fold lower affinity and require the polybasic region for plasma membrane targeting. These ARF-GEFs share a common, tripartite structure consisting of an N-terminal coiled-coil domain, a central domain with homology to the yeast protein Sec7, a PH domain, and a C-terminal polybasic region. The Sec7 domain is autoinhibited by conserved elements proximal to the PH domain. GRP1 binds to the DNA binding domain of certain nuclear receptors (TRalpha, TRbeta, AR, ER, but not RXR), and can repress thyroid hormone receptor (TR)-mediated transactivation by decreasing TR-complex formation on thyroid hormone response elements. ARNO promotes sequential activation of Arf6, Cdc42 and Rac1 and insulin secretion. Cytohesin acts as a PI 3-kinase effector mediating biological responses including cell spreading and adhesion, chemotaxis, protein trafficking, and cytoskeletal rearrangements, only some of which appear to depend on their ability to activate ARFs. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130  897 KRGVLWKkaQGTSLLGrdnFKRRTFILTDTCLSYYSGVDISEmkQKGQIPLTKIRAVEVAHATP------WGRSNMIQ-- 968
Cdd:cd01252     5 REGWLLK--LGGRVKS---WKRRWFILTDNCLYYFEYTTDKE--PRGIIPLENLSVREVEDKKKpfcfelYSPSNGQVik 77

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 167522130  969 ----------VVHDDAILYVDAESQAERQDWIDEIRSA 996
Cdd:cd01252    78 acktdsdgkvVEGNHTVYRISAASEEERDEWIKSIKAS 115

PH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130   897 KRGVLWKKaQGTSllgrdnFKRRTFILTDTCLSYYsgVDISEMKQKGQIPLTKIRAVEVAH------ATPwGRSNMIQVV 970
Cdd:pfam14593   15 KQGLVKKR-KGLF------AKKRQLILTDGPRLIY--VDPVKMVLKGEIPWSKELKVEAKNfktffiHTP-NRTYYLEDP 84

                           90
                   ....*....|
gi 167522130   971 HDDAILYVDA 980
Cdd:pfam14593   85 EGDALKWCKA 94

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130  915 NFKRRTFILTDTCLSYYSGVDISEMKQKGQIPLTkiravEVAHATPWGRSNMIQVVHDDAILYVDAESQAERQDWIDEIR 994
Cdd:cd13282    14 TWKRRWFVLKNGELFYYKSPNDVIRKPQGQIALD-----GSCEIARAEGAQTFEIVTEKRTYYLTADSENDLDEWIRVIQ 88

                  ....*..
gi 167522130  995 SACQEGQ 1001
Cdd:cd13282    89 NVLRRQA 95

Alpha helical coiled-coil rod protein (HCR); This family consists of several mammalian alpha helical coiled-coil rod HCR proteins. The function of HCR is unknown but it has been implicated in psoriasis in humans and is thought to affect keratinocyte proliferation.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130   486 SSPMASVSQPVALDMQNGLQH------------TATAELIQHIKSILLEDPRLDLENKFDVLQQLQSYVFTLEERLAAQQ 553
Cdd:pfam07111  465 SCPPPPPAPPVDADLSLELEQlreernrldaelQLSAHLIQQEVGRAREQGEAERQQLSEVAQQLEQELQRAQESLASVG 544

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130   554 QrnlELETALSNTQEQLQKRQSTLAMLDKQRTNNQSALLEMINDFHADFVEKLDRHERRFGEARttldtihSDVERQMVT 633
Cdd:pfam07111  545 Q---QLEVARQGQQESTEEAASLRQELTQQQEIYGQALQEKVAEVETRLREQLSDTKRRLNEAR-------REQAKAVVS 614

                          170       180       190
                   ....*....|....*....|....*....|.
gi 167522130   634 MRDIQTRA------NDFLQELQMKAEHLETE 658
Cdd:pfam07111  615 LRQIQHRAtqekerNQELRRLQDEARKEEGQ 645

Four phosphate adaptor protein 1 and 2 Pleckstrin homology (PH) domain; Human FAPP1 (also called PLEKHA3/Pleckstrin homology domain-containing, family A member 3) regulates secretory transport from the trans-Golgi network to the plasma membrane. It is recruited through binding of PH domain to phosphatidylinositol 4-phosphate (PtdIns(4)P) and a small GTPase ADP-ribosylation factor 1 (ARF1). These two binding sites have little overlap the FAPP1 PH domain to associate with both ligands simultaneously and independently. FAPP1 has a N-terminal PH domain followed by a short proline-rich region. FAPP1 is a member of the oxysterol binding protein (OSBP) family which includes OSBP, OSBP-related proteins (ORP), and Goodpasture antigen binding protein (GPBP). They have a wide range of purported functions including sterol transport, cell cycle control, pollen development and vessicle transport from Golgi recognize both PI lipids and ARF proteins. FAPP2 (also called PLEKHA8/Pleckstrin homology domain-containing, family A member 8), a member of the Glycolipid lipid transfer protein(GLTP) family has an N-terminal PH domain that targets the TGN and C-terminal GLTP domain. FAPP2 functions to traffic glucosylceramide (GlcCer) which is made in the Golgi. It's interaction with vesicle-associated membrane protein-associated protein (VAP) could be a means of regulation. Some FAPP2s share the FFAT-like motifs found in GLTP. 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 167522130  899 GVLWKKAQGTSllgrdNFKRRTFILTDTCLSYYSGVDisEMKQ--KGQIpltKIRAVEV-AHATPWGRSNMIqvVHDDAI 975
Cdd:cd01247     3 GVLWKWTNYLS-----GWQPRWFVLDDGVLSYYKSQE--EVNQgcKGSV---KMSVCEIiVHPTDPTRMDLI--IPGEQH 70

                          90
                  ....*....|....*
gi 167522130  976 LYVDAESQAERQDWI 990
Cdd:cd01247    71 FYLKASSAAERQRWL 85

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 167522130  897 KRGVLWKkaQGTSllGRDNFKRRTFILTDTCLSYYSGVDisEMKQKGQIPLTKIRAVEVAHATPWGRSNMIQVVHDDAIL 976
Cdd:cd13248     9 MSGWLHK--QGGS--GLKNWRKRWFVLKDNCLYYYKDPE--EEKALGSILLPSYTISPAPPSDEISRKFAFKAEHANMRT 82

                          90       100
                  ....*....|....*....|.
gi 167522130  977 YV-DAESQAERQDWIDEIRSA 996
Cdd:cd13248    83 YYfAADTAEEMEQWMNAMSLA 103

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130  897 KRGvlWKKAQGTSLlgrDNFKRRTFILTDTCLSYYSgvDISEMKQKGQIPLTKIRAVEVA-----------HATPWGRSN 965
Cdd:cd13263     5 KSG--WLKKQGSIV---KNWQQRWFVLRGDQLYYYK--DEDDTKPQGTIPLPGNKVKEVPfnpeepgkflfEIIPGGGGD 77

                          90       100       110
                  ....*....|....*....|....*....|.
gi 167522130  966 MIQVVHDDAILYvdAESQAERQDWIDEIRSA 996
Cdd:cd13263    78 RMTSNHDSYLLM--ANSQAEMEEWVKVIRRV 106

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130   510 AELIQHIKSIL--LEDPRLDLENKFDVLQQLQSYVFTLEERLAAQQQRNLELETALSNTQEQLQKRQSTLAMLDK----- 582
Cdd:TIGR02168  757 TELEAEIEELEerLEEAEEELAEAEAEIEELEAQIEQLKEELKALREALDELRAELTLLNEEAANLRERLESLERriaat 836

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130   583 --------QRTNNQSALLEMINDFHADFVEKLDRHER-------RFGEARTTLDTIHSDVERQMVTMRDIQTRANDFLQE 647
Cdd:TIGR02168  837 errledleEQIEELSEDIESLAAEIEELEELIEELESeleallnERASLEEALALLRSELEELSEELRELESKRSELRRE 916

                          170
                   ....*....|
gi 167522130   648 LQMKAEHLET 657
Cdd:TIGR02168  917 LEELREKLAQ 926

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 1; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the first PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 167522130  897 KRGVLWKKaqgtsllGRDN--FKRRTFILT--DTCLSYYSGVDISEMKQkgQIPLTKIRAVEVAHATpwGRSNMIQV--V 970
Cdd:cd13252     3 KEGFLWKR-------GKDNnqFKQRKFVLSerEGTLKYFVKEDAKEPKA--VISIEELNATFQPEKI--GHPNGLQItyL 71

                          90       100
                  ....*....|....*....|....*...
gi 167522130  971 HDDAI--LYVDAESQAERQDWIDEIRSA 996
Cdd:cd13252    72 KDGSTrnIFVYHEDGKEIVDWYNAIRAA 99