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 672040891 400 SLETSSYLNVLVNSQWKSRWCFVRDSHLHFYQDRNRGKMAQQPLSLVGCDVLPDPSPDHLYSFRILHNGEELAKLEAKSS 479
Cdd:cd13307    1 GVPTCGYLNVLVNQQWRSRWCCVKDGQLHFYQDRNKTKSPQQSLPLHGCEVVPGPDPKHPYSFRILRNGEEVAALEASSS 80

                         90       100
                 ....*....|....*....|.
gi 672040891 480 EEMGHWLGLLLSESGSKTDPE 500
Cdd:cd13307   81 EDMGRWLGVLLAETGSATDPE 101

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 672040891 400 SLETSSYLNVLVNSQWKSRWCFVRDSHLHFYQDRNRGKMAQQPLSLVGCDVLPDPSPDHLYSFRILHNGEELAKLEAKSS 479
Cdd:cd13307    1 GVPTCGYLNVLVNQQWRSRWCCVKDGQLHFYQDRNKTKSPQQSLPLHGCEVVPGPDPKHPYSFRILRNGEEVAALEASSS 80

                         90       100
                 ....*....|....*....|.
gi 672040891 480 EEMGHWLGLLLSESGSKTDPE 500
Cdd:cd13307   81 EDMGRWLGVLLAETGSATDPE 101

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 672040891   228 FLWRKKW--LGQWAKQLCVIRDTRLLCYKSSK---DHSPQLDVNLLGSSVVH-KEKQVRKKEHKLKIMPMNADVIVLGLQ 301
Cdd:smart00233   6 WLYKKSGggKKSWKKRYFVLFNSTLLYYKSKKdkkSYKPKGSIDLSGCTVREaPDPDSSKKPHCFEIKTSDRKTLLLQAE 85

                           90
                   ....*....|....*.
gi 672040891   302 SKDQAEQWLRVIQEVS 317
Cdd:smart00233  86 SEEEREKWVEALRKAI 101

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672040891  218 ELMRDARICAFLWRKKWlgqwakqlCVIRDTRLLCYKSS---KDHSPQLDVNLLGSSVVHKEKQVR-KKEHKLKI---MP 290
Cdd:pfam00169   6 WLLKKGGGKKKSWKKRY--------FVLFDGSLLYYKDDksgKSKEPKGSISLSGCEVVEVVASDSpKRKFCFELrtgER 77

                          90       100
                  ....*....|....*....|....*..
gi 672040891  291 MNADVIVLGLQSKDQAEQWLRVIQEVS 317
Cdd:pfam00169  78 TGKRTYLLQAESEEERKDWIKAIQSAI 104

DNA double-strand break repair ATPase Rad50;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672040891 723 KNRTEAEVKRYTEEKRR---LERSKEEIRGHLAQLRREKRELKETLLRCTDKGV-VAKLEQALKRIDEECRLEESRRVDL 798
Cdd:PRK03918 192 EELIKEKEKELEEVLREineISSELPELREELEKLEKEVKELEELKEEIEELEKeLESLEGSKRKLEEKIRELEERIEEL 271

                         90
                 ....*....|....*
gi 672040891 799 ELSIVEVKDNLKKAE 813
Cdd:PRK03918 272 KKEIEELEEKVKELK 286

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 672040891 400 SLETSSYLNVLVNSQWKSRWCFVRDSHLHFYQDRNRGKMAQQPLSLVGCDVLPDPSPDHLYSFRILHNGEELAKLEAKSS 479
Cdd:cd13307    1 GVPTCGYLNVLVNQQWRSRWCCVKDGQLHFYQDRNKTKSPQQSLPLHGCEVVPGPDPKHPYSFRILRNGEEVAALEASSS 80

                         90       100
                 ....*....|....*....|.
gi 672040891 480 EEMGHWLGLLLSESGSKTDPE 500
Cdd:cd13307   81 EDMGRWLGVLLAETGSATDPE 101

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 672040891   412 NSQWKSRWCFVRDSHLHFYQDR--NRGKMAQQPLSLVGCDVLPDPSPDHL---YSFRILHNGEELAKLEAKSSEEMGHWL 486
Cdd:smart00233  15 KKSWKKRYFVLFNSTLLYYKSKkdKKSYKPKGSIDLSGCTVREAPDPDSSkkpHCFEIKTSDRKTLLLQAESEEEREKWV 94

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672040891  413 SQWKSRWCFVRDSHLHFYQDRNRGKMA--QQPLSLVGC---DVLPDPSPDHLYSFRILH---NGEELAKLEAKSSEEMGH 484
Cdd:pfam00169  16 KSWKKRYFVLFDGSLLYYKDDKSGKSKepKGSISLSGCevvEVVASDSPKRKFCFELRTgerTGKRTYLLQAESEEERKD 95

                  ..
gi 672040891  485 WL 486
Cdd:pfam00169  96 WI 97

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672040891 215 ASIELMRDARICAFLWRK----KWLGQWAKQLCVIRDTRLLCYKSSKDHSPQLDVNLLGSSVVHKEKQVRKKEHKLKIMP 290
Cdd:cd13308    1 QLLTLPRDVIHSGTLTKKggsqKTLQNWQLRYVIIHQGCVYYYKNDQSAKPKGVFSLNGYNRRAAEERTSKLKFVFKIIH 80

                         90       100       110
                 ....*....|....*....|....*....|
gi 672040891 291 MNADVIVLGLQSKDQAEQ--WLRVIQEVSG 318
Cdd:cd13308   81 LSPDHRTWYFAAKSEDEMseWMEYIRREID 110

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 672040891 229 LWRKKWLGQWAKQLCVIRDTRLLCYKSSKDHSPQLD--VNLLGSSVVhKEKQVRKKEHKLKIMPMNADVIVLGLQSKDQA 306
Cdd:cd00821    7 KRGGGGLKSWKKRWFVLFEGVLLYYKSKKDSSYKPKgsIPLSGILEV-EEVSPKERPHCFELVTPDGRTYYLQADSEEER 85

                 ....*..
gi 672040891 307 EQWLRVI 313
Cdd:cd00821   86 QEWLKAL 92

Fermitin family pleckstrin homology (PH) domain; Fermitin functions as a mediator of integrin inside-out signalling. The recruitment of Fermitin proteins and Talin to the membrane mediates the terminal event of integrin signalling, via interaction with integrin beta subunits. Fermatin has FERM domain interrupted with a pleckstrin homology (PH) domain. Fermitin family homologs (Fermt1, 2, and 3, also known as Kindlins) are each encoded by a different gene. In mammalian studies, Fermt1 is generally expressed in epithelial cells, Fermt2 is expressed inmuscle tissues, and Fermt3 is expressed in hematopoietic lineages. Specifically Fermt2 is expressed in smooth and striated muscle tissues in mice and in the somites (a trunk muscle precursor) and neural crest in Xenopus embryos. As such it has been proposed that Fermt2 plays a role in cardiomyocyte and neural crest differentiation. Expression of mammalian Fermt3 is associated with hematopoietic lineages: the anterior ventral blood islands, vitelline veins, and early myeloid cells. In Xenopus embryos this expression, also include the notochord and cement gland. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 672040891 415 WKSRWCFVRDSHLHFYQDRN-RGKMAQQPLSLVGCDVLPDPSpdhlysfriLHNGEELAKLEAKSSEEM-GHWL 486
Cdd:cd01237   20 YKRYWFVFKDTHLSYYKSKEeSNGAPIQQINLKGCEVTPDVN---------VSQQKFCIKLLVPSPEGMsEVWL 84

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672040891 710 DKLRVTSAEIKLGKNRTEAEVKRYTEEKRRLERSKEEIRGHLAQLRREKRELKETLLRCTDKgvVAKLEQALKRIDEECR 789
Cdd:COG1196  235 RELEAELEELEAELEELEAELEELEAELAELEAELEELRLELEELELELEEAQAEEYELLAE--LARLEQDIARLEERRR 312

                         90       100
                 ....*....|....*....|....*
gi 672040891 790 LEESRRVDLELSIVEVKDNLKKAEA 814
Cdd:COG1196  313 ELEERLEELEEELAELEEELEELEE 337

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 672040891 229 LWRKKWlgqwakqlCVIRDTRLLCYKSSKDHSPQLDVNLLGSSV--VHKEKQVRKKeHKLKIMPMNADVIVLGLQSKDQA 306
Cdd:cd13248   23 NWRKRW--------FVLKDNCLYYYKDPEEEKALGSILLPSYTIspAPPSDEISRK-FAFKAEHANMRTYYFAADTAEEM 93

                         90
                 ....*....|.
gi 672040891 307 EQWLRVIQEVS 317
Cdd:cd13248   94 EQWMNAMSLAA 104