Actin filament associated protein family Pleckstrin homology (PH) domain, repeat 1; There are 3 members of the AFAP family of adaptor proteins: AFAP1, AFAP1L1, and AFAP1L2/XB130. AFAP1 is a cSrc binding partner and actin cross-linking protein. AFAP1L1 is thought to play a similar role to AFAP1 in terms of being an actin cross-linking protein, but it preferentially binds to cortactin and not cSrc, thereby playing a role in invadosome formation. AFAP1L2 is a cSrc binding protein, but does not bind to actin filaments. AFAP1L2 acts as an intermediary between the RET/PTC kinase and PI-3kinase pathway in the thyroid. The AFAPs share a similar structure of a SH3 binding motif, 3 SH2 binding motifs, 2 PH domains, a coiled-coil region corresponding to the AFAP1 leucine zipper, and an actin binding domain. The amino terminal PH1 domain of AFAP1 has been known to function in intra-molecular regulation of AFAP1. In addition, the PH1 domain is a binding partner for PKCa and phospholipids. This cd is the first PH domain of AFAP. 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 1995160307 142 SEEASMDLVKDAKICAFLLRKKRFGQWTKLLCVIKDTKLLCYKSSKDQQPQMELPLQGCSITYIPRDSKKKKHELKITQQ 221
Cdd:cd13306     1 SEEASMELVKDARICAFLLRKKRFGQWAKQLCVIKDNRLLCYKSSKDQQPQLELPLLGCSVIYVPKDGRRKKHELKFTPP 80

                          90       100
                  ....*....|....*....|....*..
gi 1995160307 222 GTDPLVLAVQSKEQAEQWLKVIKEAYS 248
Cdd:cd13306    81 GAEALVLAVQSKEQAEQWLKVIREVSS 107

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 552 EQYKYGKNRVEADAKRLQSKEEELLKRKEALRNRLAQLRKERKDLRAAI-----EVNAGRKTQVALEDKLKRLEEECKQR 626
Cdd:COG1196   270 EELRLELEELELELEEAQAEEYELLAELARLEQDIARLEERRRELEERLeeleeELAELEEELEELEEELEELEEELEEA 349

                          90       100
                  ....*....|....*....|...
gi 1995160307 627 EAERVSLELELTEVKESLKKALA 649
Cdd:COG1196   350 EEELEEAEAELAEAEEALLEAEA 372

Actin filament associated protein family Pleckstrin homology (PH) domain, repeat 1; There are 3 members of the AFAP family of adaptor proteins: AFAP1, AFAP1L1, and AFAP1L2/XB130. AFAP1 is a cSrc binding partner and actin cross-linking protein. AFAP1L1 is thought to play a similar role to AFAP1 in terms of being an actin cross-linking protein, but it preferentially binds to cortactin and not cSrc, thereby playing a role in invadosome formation. AFAP1L2 is a cSrc binding protein, but does not bind to actin filaments. AFAP1L2 acts as an intermediary between the RET/PTC kinase and PI-3kinase pathway in the thyroid. The AFAPs share a similar structure of a SH3 binding motif, 3 SH2 binding motifs, 2 PH domains, a coiled-coil region corresponding to the AFAP1 leucine zipper, and an actin binding domain. The amino terminal PH1 domain of AFAP1 has been known to function in intra-molecular regulation of AFAP1. In addition, the PH1 domain is a binding partner for PKCa and phospholipids. This cd is the first PH domain of AFAP. 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 1995160307 142 SEEASMDLVKDAKICAFLLRKKRFGQWTKLLCVIKDTKLLCYKSSKDQQPQMELPLQGCSITYIPRDSKKKKHELKITQQ 221
Cdd:cd13306     1 SEEASMELVKDARICAFLLRKKRFGQWAKQLCVIKDNRLLCYKSSKDQQPQLELPLLGCSVIYVPKDGRRKKHELKFTPP 80

                          90       100
                  ....*....|....*....|....*..
gi 1995160307 222 GTDPLVLAVQSKEQAEQWLKVIKEAYS 248
Cdd:cd13306    81 GAEALVLAVQSKEQAEQWLKVIREVSS 107

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307  158 FLLRKK--RFGQWTKLLCVIKDTKLLCYKSSKDQQ---PQMELPLQGCSITYIP-RDSKKKKHELKITQQGTDPLVLAVQ 231
Cdd:smart00233   6 WLYKKSggGKKSWKKRYFVLFNSTLLYYKSKKDKKsykPKGSIDLSGCTVREAPdPDSSKKPHCFEIKTSDRKTLLLQAE 85

                           90
                   ....*....|....*
gi 1995160307  232 SKEQAEQWLKVIKEA 246
Cdd:smart00233  86 SEEEREKWVEALRKA 100

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 154 KICAFLLRKK--RFGQWTKLLCVIKDTKLLCYKSS---KDQQPQMELPLQGCSITYIPR-DSKKKKHELKI---TQQGTD 224
Cdd:pfam00169   2 VKEGWLLKKGggKKKSWKKRYFVLFDGSLLYYKDDksgKSKEPKGSISLSGCEVVEVVAsDSPKRKFCFELrtgERTGKR 81

                          90       100
                  ....*....|....*....|..
gi 1995160307 225 PLVLAVQSKEQAEQWLKVIKEA 246
Cdd:pfam00169  82 TYLLQAESEEERKDWIKAIQSA 103

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 552 EQYKYGKNRVEADAKRLQSKEEELLKRKEALRNRLAQLRKERKDLRAAI-----EVNAGRKTQVALEDKLKRLEEECKQR 626
Cdd:COG1196   270 EELRLELEELELELEEAQAEEYELLAELARLEQDIARLEERRRELEERLeeleeELAELEEELEELEEELEELEEELEEA 349

                          90       100
                  ....*....|....*....|...
gi 1995160307 627 EAERVSLELELTEVKESLKKALA 649
Cdd:COG1196   350 EEELEEAEAELAEAEEALLEAEA 372

phosphodiesterase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 552 EQYKYGKNRVEADAKR----LQSKEEELLKRKEALRNRLAQLRKERKDLraaievNAGRKTQVALEDKLKRLEEECKQRE 627
Cdd:PRK12704   64 EEIHKLRNEFEKELRErrneLQKLEKRLLQKEENLDRKLELLEKREEEL------EKKEKELEQKQQELEKKEEELEELI 137

                          90       100
                  ....*....|....*....|...
gi 1995160307 628 AERVsLELE----LT--EVKESL 644
Cdd:PRK12704  138 EEQL-QELErisgLTaeEAKEIL 159

Ezrin/radixin/moesin, alpha-helical domain; The ERM family consists of three closely-related proteins, ezrin, radixin and moesin. Ezrin was first identified as a constituent of microvilli, radixin as a barbed, end-capping actin-modulating protein from isolated junctional fractions, and moesin as a heparin binding protein. A tumour suppressor molecule responsible for neurofibromatosis type 2 (NF2) is highly similar to ERM proteins and has been designated merlin (moesin-ezrin-radixin-like protein). ERM molecules contain 3 domains, an N-terminal globular domain, an extended alpha-helical domain and a charged C-terminal domain (pfam00769). Ezrin, radixin and merlin also contain a polyproline linker region between the helical and C-terminal domains. The N-terminal domain is highly conserved and is also found in merlin, band 4.1 proteins and members of the band 4.1 superfamily, designated the FERM domain. ERM proteins crosslink actin filaments with plasma membranes. They co-localize with CD44 at actin filament plasma membrane interaction sites, associating with CD44 via their N-terminal domains and with actin filaments via their C-terminal domains. This is the alpha-helical domain, which is involved in intramolecular masking of protein-protein interaction sites, regulating the activity of this proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 566 KRLQSKEEELLKRKEALR---NRLAQLRKERKDLRAAIEVNAgrKTQVALEDKLKRLEEECKQREAERVSLELELTEVKE 642
Cdd:pfam20492  13 ERLKQYEEETKKAQEELEeseETAEELEEERRQAEEEAERLE--QKRQEAEEEKERLEESAEMEAEEKEQLEAELAEAQE 90

Actin filament associated protein family Pleckstrin homology (PH) domain, repeat 1; There are 3 members of the AFAP family of adaptor proteins: AFAP1, AFAP1L1, and AFAP1L2/XB130. AFAP1 is a cSrc binding partner and actin cross-linking protein. AFAP1L1 is thought to play a similar role to AFAP1 in terms of being an actin cross-linking protein, but it preferentially binds to cortactin and not cSrc, thereby playing a role in invadosome formation. AFAP1L2 is a cSrc binding protein, but does not bind to actin filaments. AFAP1L2 acts as an intermediary between the RET/PTC kinase and PI-3kinase pathway in the thyroid. The AFAPs share a similar structure of a SH3 binding motif, 3 SH2 binding motifs, 2 PH domains, a coiled-coil region corresponding to the AFAP1 leucine zipper, and an actin binding domain. The amino terminal PH1 domain of AFAP1 has been known to function in intra-molecular regulation of AFAP1. In addition, the PH1 domain is a binding partner for PKCa and phospholipids. This cd is the first PH domain of AFAP. 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 1995160307 142 SEEASMDLVKDAKICAFLLRKKRFGQWTKLLCVIKDTKLLCYKSSKDQQPQMELPLQGCSITYIPRDSKKKKHELKITQQ 221
Cdd:cd13306     1 SEEASMELVKDARICAFLLRKKRFGQWAKQLCVIKDNRLLCYKSSKDQQPQLELPLLGCSVIYVPKDGRRKKHELKFTPP 80

                          90       100
                  ....*....|....*....|....*..
gi 1995160307 222 GTDPLVLAVQSKEQAEQWLKVIKEAYS 248
Cdd:cd13306    81 GAEALVLAVQSKEQAEQWLKVIREVSS 107

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307  158 FLLRKK--RFGQWTKLLCVIKDTKLLCYKSSKDQQ---PQMELPLQGCSITYIP-RDSKKKKHELKITQQGTDPLVLAVQ 231
Cdd:smart00233   6 WLYKKSggGKKSWKKRYFVLFNSTLLYYKSKKDKKsykPKGSIDLSGCTVREAPdPDSSKKPHCFEIKTSDRKTLLLQAE 85

                           90
                   ....*....|....*
gi 1995160307  232 SKEQAEQWLKVIKEA 246
Cdd:smart00233  86 SEEEREKWVEALRKA 100

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 1995160307 352 CGYLNVLSN---SRWRERWCRVKDSKLILHKDRAD-LKTHIVSIPLRG-CEVIPGLDSKHPLTFRLLRNGQEVAVLEASS 426
Cdd:cd00821     2 EGYLLKRGGgglKSWKKRWFVLFEGVLLYYKSKKDsSYKPKGSIPLSGiLEVEEVSPKERPHCFELVTPDGRTYYLQADS 81

                          90
                  ....*....|.
gi 1995160307 427 SEDMGRWIGIL 437
Cdd:cd00821    82 EEERQEWLKAL 92

Actin filament associated protein family Pleckstrin homology (PH) domain, repeat 2; There are 3 members of the AFAP family of adaptor proteins: AFAP1, AFAP1L1, and AFAP1L2/XB130. AFAP1 is a cSrc binding partner and actin cross-linking protein. AFAP1L1 is thought to play a similar role to AFAP1 in terms of being an actin cross-linking protein, but it preferentially binds to cortactin and not cSrc, thereby playing a role in invadosome formation. AFAP1L2 is a cSrc binding protein, but does not bind to actin filaments. AFAP1L2 acts as an intermediary between the RET/PTC kinase and PI-3kinase pathway in the thyroid. The AFAPs share a similar structure of a SH3 binding motif, 3 SH2 binding motifs, 2 PH domains, a coiled-coil region corresponding to the AFAP1 leucine zipper, and an actin binding domain. This cd is the second PH domain of AFAP. 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 1995160307 166 GQWTKLLCVIKDTKLLCYKS-SKDQQPQMELPLQGCSItyIPRDSKKKKHELKITQQGTDPLVLAVQSKEQAEQWLKV-I 243
Cdd:cd13307    14 QQWRSRWCCVKDGQLHFYQDrNKTKSPQQSLPLHGCEV--VPGPDPKHPYSFRILRNGEEVAALEASSSEDMGRWLGVlL 91

                          90
                  ....*....|....
gi 1995160307 244 KEAYSGCsgpvDPE 257
Cdd:cd13307    92 AETGSAT----DPE 101

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 352 CGYLNVLSN---SRWRERWCRVKDSKLILHKDRADLKTHI--VSIPLRGCEVIPGLDS---KHPLTFRLL---RNGQEVA 420
Cdd:pfam00169   4 EGWLLKKGGgkkKSWKKRYFVLFDGSLLYYKDDKSGKSKEpkGSISLSGCEVVEVVASdspKRKFCFELRtgeRTGKRTY 83

                          90
                  ....*....|....
gi 1995160307 421 VLEASSSEDMGRWI 434
Cdd:pfam00169  84 LLQAESEEERKDWI 97

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 1995160307 167 QWTKLLCVIKDTKLLCYKSSKDQQPQMELPLQGCSIT-YIPRDSKKKKHELKITQQGTDPLVLAVQSKEQAEQWLKVIKE 245
Cdd:cd13248    23 NWRKRWFVLKDNCLYYYKDPEEEKALGSILLPSYTISpAPPSDEISRKFAFKAEHANMRTYYFAADTAEEMEQWMNAMSL 102

                  .
gi 1995160307 246 A 246
Cdd:cd13248   103 A 103

Anillin Pleckstrin homology (PH) domain; Anillin (Rhotekin/RTKN; also called PLEKHK/Pleckstrin homology domain-containing family K) is an actin binding protein involved in cytokinesis. It interacts with GTP-bound Rho proteins and results in the inhibition of their GTPase activity. Dysregulation of the Rho signal transduction pathway has been implicated in many forms of cancer. Anillin proteins have a N-terminal HRI domain/ACC (anti-parallel coiled-coil) finger domain or Rho-binding domain binds small GTPases from the Rho family. The C-terminal PH domain helps target anillin to ectopic septin containing foci. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 168 WTKLLCVIKDTKLLCYKSSKDQQPQMElPLQGCSIT------YIPRDSKKKKHELKITQQGTDP---LVLAVQSKEQAEQ 238
Cdd:cd13249    20 WTRLYCVLKGGNLLCYYSPEEIEAKVE-PLLTIPINketrirAVEKDSKGRASSLSIINPYSGEevtHVLSADSREELQK 98

                  ..
gi 1995160307 239 WL 240
Cdd:cd13249    99 WM 100

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 1995160307 156 CAFLLRKKRFGQ-----WTKLLCVIKDTKLLCYKSSKDQQPQMELPLQGCSITYIPRDSKKKKHEL--KITQQGTDPLVL 228
Cdd:cd13266     4 AGYLEKRRKDHSffgseWQKRWCAISKNVFYYYGSDKDKQQKGEFAINGYDVRMNPTLRKDGKKDCcfELVCPDKRTYQF 83

                          90
                  ....*....|....*.
gi 1995160307 229 AVQSKEQAEQWLKVIK 244
Cdd:cd13266    84 TAASPEDAEDWVDQIS 99

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 1995160307 347 EDVPTCGYLNVLSN--SRWRERWCRVKDSKLILHKDRADLKtHIVSIPLRGC-----------------EVIPGLDSKHP 407
Cdd:cd13263     1 ERPIKSGWLKKQGSivKNWQQRWFVLRGDQLYYYKDEDDTK-PQGTIPLPGNkvkevpfnpeepgkflfEIIPGGGGDRM 79

                          90       100
                  ....*....|....*....|....*..
gi 1995160307 408 ltfrllRNGQEVAVLEASSSEDMGRWI 434
Cdd:cd13263    80 ------TSNHDSYLLMANSQAEMEEWV 100

Septal ring factor EnvC, activator of murein hydrolases AmiA and AmiB [Cell cycle control, cell division, chromosome partitioning];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 563 ADAKRLQSKEEELLKRKEALRNRLAQLRKERKDLRAAIE-----VNAGRKTQVALEDKLKRLEEECKQREAERVSLELEL 637
Cdd:COG4942    20 DAAAEAEAELEQLQQEIAELEKELAALKKEEKALLKQLAalerrIAALARRIRALEQELAALEAELAELEKEIAELRAEL 99

                          90
                  ....*....|..
gi 1995160307 638 TEVKESLKKALA 649
Cdd:COG4942   100 EAQKEELAELLR 111

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 1995160307 348 DVPTCGYLNVLSNSR---WRERWCRVKDSKLILHKDRADLKThIVSIPLRG---CEVIPGLDSKHPLTFRLLRNGQEVAV 421
Cdd:cd13248     6 PVVMSGWLHKQGGSGlknWRKRWFVLKDNCLYYYKDPEEEKA-LGSILLPSytiSPAPPSDEISRKFAFKAEHANMRTYY 84

                          90
                  ....*....|...
gi 1995160307 422 LEASSSEDMGRWI 434
Cdd:cd13248    85 FAADTAEEMEQWM 97

Pleckstrin 2 Pleckstrin homology (PH) domain, repeat 1; Pleckstrin is a protein found in platelets. This name is derived from platelet and leukocyte C kinase substrate and the KSTR string of amino acids. Pleckstrin 2 contains two PH domains and a DEP (dishvelled, egl-10, and pleckstrin) domain. Unlike pleckstrin 1, pleckstrin 2 does not contain obvious sites of PKC phosphorylation. Pleckstrin 2 plays a role in actin rearrangement, large lamellipodia and peripheral ruffle formation, and may help orchestrate cytoskeletal arrangement. The PH domains of pleckstrin 2 are thought to contribute to lamellipodia formation. This cd contains the first PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 158 FLLRKKRFGQ-WTKLLCVIKDTKLLCYKSSKDQQPQMELPLQGCSITYIPRDSKKKKHELKITQQGTDPLVLAVQSKEQA 236
Cdd:cd13301     8 YLVKKGHVVNnWKARWFVLKEDGLEYYKKKTDSSPKGMIPLKGCTITSPCLEYGKRPLVFKLTTAKGQEHFFQACSREER 87

                          90
                  ....*....|....*.
gi 1995160307 237 EQWLKVIKEAYSGCSG 252
Cdd:cd13301    88 DAWAKDITKAITCLEG 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 1995160307 160 LRKKR--FGQWTKLLCVIKDTKLLCYKSSKDQQPQMELPLQGCSI---TYIPRDSKKKKHELKITQQGT------DPLVL 228
Cdd:cd13263     9 LKKQGsiVKNWQQRWFVLRGDQLYYYKDEDDTKPQGTIPLPGNKVkevPFNPEEPGKFLFEIIPGGGGDrmtsnhDSYLL 88

                          90       100
                  ....*....|....*....|....
gi 1995160307 229 AVQSKEQAEQWLKVIKEAYSGCSG 252
Cdd:cd13263    89 MANSQAEMEEWVKVIRRVIGSPFG 112

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 1995160307 561 VEADAKRLQSKEEELLKRKEALRNRLAQLR--KERKDLRAAIEVNAGRKTQvaLEDKLKRLEEECKQREAERVSLELELT 638
Cdd:COG1579    57 LEKEIKRLELEIEEVEARIKKYEEQLGNVRnnKEYEALQKEIESLKRRISD--LEDEILELMERIEELEEELAELEAELA 134

                          90
                  ....*....|.
gi 1995160307 639 EVKESLKKALA 649
Cdd:COG1579   135 ELEAELEEKKA 145

phosphodiesterase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 552 EQYKYGKNRVEADAKR----LQSKEEELLKRKEALRNRLAQLRKERKDLraaievNAGRKTQVALEDKLKRLEEECKQRE 627
Cdd:PRK12704   64 EEIHKLRNEFEKELRErrneLQKLEKRLLQKEENLDRKLELLEKREEEL------EKKEKELEQKQQELEKKEEELEELI 137

                          90       100
                  ....*....|....*....|...
gi 1995160307 628 AERVsLELE----LT--EVKESL 644
Cdd:PRK12704  138 EEQL-QELErisgLTaeEAKEIL 159

Beta-spectrin pleckstrin homology (PH) domain; Beta spectrin binds actin and functions as a major component of the cytoskeleton underlying cellular membranes. Beta spectrin consists of multiple spectrin repeats followed by a PH domain, which binds to inositol-1,4,5-trisphosphate. The PH domain of beta-spectrin is thought to play a role in the association of spectrin with the plasma membrane of cells. 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 1995160307 158 FLLRK-----------KRfgQWTKLLCVIKDTKLLCYKSSKDQQPQM----ELP--LQGCSITyIPRDSKKKKHELKI-T 219
Cdd:cd10571     4 FLERKhewesggkkasNR--SWKNVYTVLRGQELSFYKDQKAAKSGItyaaEPPlnLYNAVCE-VASDYTKKKHVFRLkL 80

                          90       100
                  ....*....|....*....|....*..
gi 1995160307 220 QQGTDPLVLAvQSKEQAEQWLKVIKEA 246
Cdd:cd10571    81 SDGAEFLFQA-KDEEEMNQWVKKISFA 106

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins pleckstrin homology (PH) domain, C-terminus; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Not much is known about FGD2. FGD1 is the best characterized member of the group with mutations here leading to the X-linked disorder known as faciogenital dysplasia (FGDY). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. However, FGD1 and FGD3 induced significantly different morphological changes in HeLa Tet-Off cells and while FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTP-bound Cdc42 was significantly increased by the inducible expression of FGD3. They also reciprocally regulated cell motility in inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migration while FGD3 inhibited it. FGD1 and FGD3 therefore play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway through SCF(FWD1/beta-TrCP). FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. 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 1995160307 352 CGYLNVLSNSR-WRERWCRVKDSK---LILHKDRADLKTHiVSIPLRGCEVIP-----GLDSKHplTFRlLRNGQEVAVL 422
Cdd:cd13236    11 CGFLQYSEKGKtWQKVWCVIPRTEplvLYLYGAPQDVRAQ-RTIPLPGCEVTVpppeeRLDGRH--VFK-LSQSKQSHYF 86

                          90
                  ....*....|....*
gi 1995160307 423 EASSSEDMGRWIGIL 437
Cdd:cd13236    87 SAESEELQQRWLEAL 101

Septal ring factor EnvC, activator of murein hydrolases AmiA and AmiB [Cell cycle control, cell division, chromosome partitioning];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 559 NRVEADAKRLQSKEEELLKRKEALRNRLAQLRKERKDLRAAIevNAGRKTQVALEDKLKRLEEECKQREAERVSLELELT 638
Cdd:COG4942   153 EELRADLAELAALRAELEAERAELEALLAELEEERAALEALK--AERQKLLARLEKELAELAAELAELQQEAEELEALIA 230

                  ....*....
gi 1995160307 639 EVKESLKKA 647
Cdd:COG4942   231 RLEAEAAAA 239

FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 2; Members here include FARP1 (also called Chondrocyte-derived ezrin-like protein; PH domain-containing family C member 2), FARP2 (also called FIR/FERM domain including RhoGEF; FGD1-related Cdc42-GEF/FRG), and FARP6 (also called Zinc finger FYVE domain-containing protein 24). They are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. Little is known about FARP1 and FARP6, though FARP1 has increased expression in differentiated chondrocytes. FARP2 is thought to regulate neurite remodeling by mediating the signaling pathways from membrane proteins to Rac. It is found in brain, lung, and testis, as well as embryonic hippocampal and cortical neurons. FARP1 and FARP2 are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. FARP6 is composed of Dbl-homology (DH), and two C-terminal PH domains separated by a FYVE domain. This hierarchy contains the second PH repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 155 ICAFLLRK-KRFGQWTKLLCVIKDTKLLCYKSSKDQQPQMELPLQGCSITYI-PRDSKKKKHELKItQQGTDPLVLAVQS 232
Cdd:cd13235     5 MSGYLLRKfKNSNGWQKLWVVFTNFCLFFYKSHQDEFPLASLPLLGYSVGLPsEADNIDKDYVFKL-QFKSHVYFFRAES 83

                          90
                  ....*....|....
gi 1995160307 233 KEQAEQWLKVIKEA 246
Cdd:cd13235    84 EYTFERWMEVIRSA 97

Src kinase-associated phosphoprotein 1 Pleckstrin homology (PH) domain; Adaptor protein Skap1 (also called Skap55/Src kinase-associated phosphoprotein of 55 kDa) and its partner, ADAP (adhesion and degranulation promoting adapter protein) help reorganize the cytoskeleton and/or promote integrin-mediated adhesion upon immunoreceptor activation. Skap1 is also involved in T Cell Receptor (TCR)-induced RapL-Rap1 complex formation and LFA-1 activation. Skap1 has an N-terminal coiled-coil conformation which is proposed to be involved in homodimer formation, a central PH domain and a C-terminal SH3 domain that associates with ADAP. The Skap1 PH domain plays a role in controlling integrin function via recruitment of ADAP-SKAP complexes to integrins as well as in controlling the ability of ADAP to interact with the CBM signalosome and regulate NF-kappaB. SKAP1 is necessary for RapL binding to membranes in a PH domain-dependent manner and the PI3K pathway. Skap adaptor proteins couple receptors to cytoskeletal rearrangements. Skap55/Skap1, Skap2, and Skap-homology (Skap-hom) have an N-terminal coiled-coil conformation, a central PH domain and a C-terminal SH3 domain. Their PH domains bind 3'-phosphoinositides as well as directly affecting targets such as in Skap55 where it directly affecting integrin regulation by ADAP and NF-kappaB activation or in Skap-hom where the dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch that controls ruffle formation. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 158 FLLRKKR----FG-QWTKLLCVIKDTKLLCYKSSKDQQPQMELPLQGCSITYIP---RDSKKKKHeLKITQQGTDPLVLA 229
Cdd:cd13380     6 YLEKRSKdhsfFGsEWQKRWCVLTNRAFYYYASEKSKQPKGGFLIKGYSAQMAPhlrKDSRRDSC-FELTTPGRRTYQFT 84

                          90
                  ....*....|....
gi 1995160307 230 VQSKEQAEQWLKVI 243
Cdd:cd13380    85 AASPSEARDWVDQI 98

Ezrin/radixin/moesin, alpha-helical domain; The ERM family consists of three closely-related proteins, ezrin, radixin and moesin. Ezrin was first identified as a constituent of microvilli, radixin as a barbed, end-capping actin-modulating protein from isolated junctional fractions, and moesin as a heparin binding protein. A tumour suppressor molecule responsible for neurofibromatosis type 2 (NF2) is highly similar to ERM proteins and has been designated merlin (moesin-ezrin-radixin-like protein). ERM molecules contain 3 domains, an N-terminal globular domain, an extended alpha-helical domain and a charged C-terminal domain (pfam00769). Ezrin, radixin and merlin also contain a polyproline linker region between the helical and C-terminal domains. The N-terminal domain is highly conserved and is also found in merlin, band 4.1 proteins and members of the band 4.1 superfamily, designated the FERM domain. ERM proteins crosslink actin filaments with plasma membranes. They co-localize with CD44 at actin filament plasma membrane interaction sites, associating with CD44 via their N-terminal domains and with actin filaments via their C-terminal domains. This is the alpha-helical domain, which is involved in intramolecular masking of protein-protein interaction sites, regulating the activity of this proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307 566 KRLQSKEEELLKRKEALR---NRLAQLRKERKDLRAAIEVNAgrKTQVALEDKLKRLEEECKQREAERVSLELELTEVKE 642
Cdd:pfam20492  13 ERLKQYEEETKKAQEELEeseETAEELEEERRQAEEEAERLE--QKRQEAEEEKERLEESAEMEAEEKEQLEAELAEAQE 90

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1995160307 584 NRLAQLRKERKDLRAaiEVNAGRKTQVALEDKLKRLEEECKQREAERVSLELELTEVKESLKKA 647
Cdd:COG1579    17 SELDRLEHRLKELPA--ELAELEDELAALEARLEAAKTELEDLEKEIKRLELEIEEVEARIKKY 78

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1995160307  560 RVEADAKRLQSKEEELlKRKEALRNRLAQLRKERKDLRAAIEVNAGRKTQVALEDKLKRLEEECKQREAERVSLELELTE 639
Cdd:COG4913    256 PIRELAERYAAARERL-AELEYLRAALRLWFAQRRLELLEAELEELRAELARLEAELERLEARLDALREELDELEAQIRG 334