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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 381 PELADYLRFMKPRKFTLKSYKRYFFVFKDTRLAIYKSKDERLGPPAIAINLKGCEVTPDVNLSQRRYGIKLEVPAQEGMV 460
Cdd:cd01237     1 PELADYLKYFKPKKFTLKGYKRYWFVFKDTHLSYYKSKEESNGAPIQQINLKGCEVTPDVNVSQQKFCIKLLVPSPEGMS 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1557985609 461 EYLIRCDAEEQYAKWMAAFHMASKGKTMADASFDSEVKQILDLLS 505
Cdd:cd01237    81 EVWLRCDNEDQYAKWMAACRLASKGKTMADSSYDSEVSSILAFLS 125

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in the kindlin family; The kindlin family is composed of kindlin-1, 2 and 3, which are FERM domain-containing adaptor molecules that interact with the cytoplasmic component of integrins and regulate cell-matrix connections. Kindlins belong to the 4.1- ezrin-ridixin-moesin (FERM) domain containing protein family. They contain F1, F2 and F3 subdomains that typify FERM family members, and these subdomains are preceded by an N-terminal F0 subdomain. Both F0 and F1 domains have similar ubiquitin-like folds. This family corresponds to the F0 domain. In addition, a distinctive feature of kindlins is the insertion of a pleckstrin homology (PH) subdomain into the F2 subdomain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609  12 SWELKIFVTDLKVERTLRVKGDLHIGGVMLKLVEDLDVALDWSDHALWWPKKNMWLSRTRTTLDQYGVQADSMLHFTPMH 91
Cdd:cd17095     1 SWELSITVTDLQIERKLRVTGDLHIGGVMLKLVETLGVAQDWSDHALWWPQKRVWLLKTRSTLDQYGVQADAELHFTPMH 80

FERM central domain; This domain is the central structural domain of the FERM domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 464 IRCDaEEQYAKwMAAFHMASKGKTMADASFDSEVKQILDLLSMQHpapapaispnqininpedyiaprfLRKLKSRgQII 543
Cdd:pfam00373  28 LPCS-EEEALL-LAALQLQAEFGDYQPSSHTSEYLSLESFLPKQL------------------------LRKMKSK-ELE 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1557985609 544 QRILEAHANVKDLNSVEAKLNFIKAWQALPEYGISLF 580
Cdd:pfam00373  81 KRVLEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 381 PELADYLRFMKPRKFTLKSYKRYFFVFKDTRLAIYKSKDERLGPPAIAINLKGCEVTPDVNLSQRRYGIKLEVPAQEGMV 460
Cdd:cd01237     1 PELADYLKYFKPKKFTLKGYKRYWFVFKDTHLSYYKSKEESNGAPIQQINLKGCEVTPDVNVSQQKFCIKLLVPSPEGMS 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1557985609 461 EYLIRCDAEEQYAKWMAAFHMASKGKTMADASFDSEVKQILDLLS 505
Cdd:cd01237    81 EVWLRCDNEDQYAKWMAACRLASKGKTMADSSYDSEVSSILAFLS 125

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in the kindlin family; The kindlin family is composed of kindlin-1, 2 and 3, which are FERM domain-containing adaptor molecules that interact with the cytoplasmic component of integrins and regulate cell-matrix connections. Kindlins belong to the 4.1- ezrin-ridixin-moesin (FERM) domain containing protein family. They contain F1, F2 and F3 subdomains that typify FERM family members, and these subdomains are preceded by an N-terminal F0 subdomain. Both F0 and F1 domains have similar ubiquitin-like folds. This family corresponds to the F0 domain. In addition, a distinctive feature of kindlins is the insertion of a pleckstrin homology (PH) subdomain into the F2 subdomain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609  12 SWELKIFVTDLKVERTLRVKGDLHIGGVMLKLVEDLDVALDWSDHALWWPKKNMWLSRTRTTLDQYGVQADSMLHFTPMH 91
Cdd:cd17095     1 SWELSITVTDLQIERKLRVTGDLHIGGVMLKLVETLGVAQDWSDHALWWPQKRVWLLKTRSTLDQYGVQADAELHFTPMH 80

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in the kindlin family; The kindlin family is composed of Kindlin-1, 2 and 3, which are FERM domain-containing adaptor molecules that interact with the cytoplasmic component of integrins and regulate cell-matrix connections. Kindlins belong to the 4.1- ezrin-ridixin-moesin (FERM) domain containing protein family. They contain F1, F2 and F3 subdomains that typify FERM family members, and these subdomains are preceded by an N-terminal F0 subdomain. Both F0 and F1 domains have similar ubiquitin-like folds. This family corresponds to the F1 domain. In addition, a distinctive feature of kindlins is the insertion of a pleckstrin homology (PH) subdomain into the F2 subdomain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609  92 KTLRIQLPDLRFMDAKVDFSVQCFSAVVQLCKDLGIRHPEELSFCRPLcpehlkknykyagvsprqrakdamgpivqnnp 171
Cdd:cd17096     1 KTLRIQLPDLQYLDLRVDFSVKVFNAVVDLCKELGIRHPEELSLLRPP-------------------------------- 48

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 172 yasnistpdgksspavdlnttpvshlngsagsfspisnghstsfdnsfymgsdpsipslasspqtptleakntLIRPKSL 251
Cdd:cd17096    49 -------------------------------------------------------------------------LYRPKSL 55

                         170       180       190
                  ....*....|....*....|....*....|....*
gi 1557985609 252 VERARLNCGWLDSSLSLYEQDVREFDLLLLRFKFY 286
Cdd:cd17096    56 VDKARLNSGWLDSSRSLMEQGVRENDTLLLRFKYY 90

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 390 MKPRKFTLKSYKRYFFVFKDTRLAIYKSKDE-RLGPPAIAINLKGCEVTPDVNLSQ--RRYGIKLEVPAQEGMVEYLIRC 466
Cdd:pfam00169   8 LKKGGGKKKSWKKRYFVLFDGSLLYYKDDKSgKSKEPKGSISLSGCEVVEVVASDSpkRKFCFELRTGERTGKRTYLLQA 87

                          90
                  ....*....|....*...
gi 1557985609 467 DAEEQYAKWMAAFHMASK 484
Cdd:pfam00169  88 ESEEERKDWIKAIQSAIR 105

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609  261 WLDSSLSLYEQDVREFDL-LLLRFKFYSFYDLNPKLDSARINQIYEQARWSLLTEEIECTEEEMMMFASLNLQVNLQSNS 339
Cdd:smart00295  55 WLDPAKTLLDQDVKSEPLtLYFRVKFYPPDPNQLKEDPTRLNLLYLQVRNDILEGRLPCPEEEALLLAALALQAEFGDYD 134

                   .
gi 1557985609  340 P 340
Cdd:smart00295 135 E 135

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 381 PELADYLRFMKPRKFTLKSYKRYFFVFKDTRLAIYKSKDERLGPPAIAINLKGCEVTPDVNLSQRRYGIKLEVPAQEGMV 460
Cdd:cd01237     1 PELADYLKYFKPKKFTLKGYKRYWFVFKDTHLSYYKSKEESNGAPIQQINLKGCEVTPDVNVSQQKFCIKLLVPSPEGMS 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1557985609 461 EYLIRCDAEEQYAKWMAAFHMASKGKTMADASFDSEVKQILDLLS 505
Cdd:cd01237    81 EVWLRCDNEDQYAKWMAACRLASKGKTMADSSYDSEVSSILAFLS 125

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in the kindlin family; The kindlin family is composed of kindlin-1, 2 and 3, which are FERM domain-containing adaptor molecules that interact with the cytoplasmic component of integrins and regulate cell-matrix connections. Kindlins belong to the 4.1- ezrin-ridixin-moesin (FERM) domain containing protein family. They contain F1, F2 and F3 subdomains that typify FERM family members, and these subdomains are preceded by an N-terminal F0 subdomain. Both F0 and F1 domains have similar ubiquitin-like folds. This family corresponds to the F0 domain. In addition, a distinctive feature of kindlins is the insertion of a pleckstrin homology (PH) subdomain into the F2 subdomain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609  12 SWELKIFVTDLKVERTLRVKGDLHIGGVMLKLVEDLDVALDWSDHALWWPKKNMWLSRTRTTLDQYGVQADSMLHFTPMH 91
Cdd:cd17095     1 SWELSITVTDLQIERKLRVTGDLHIGGVMLKLVETLGVAQDWSDHALWWPQKRVWLLKTRSTLDQYGVQADAELHFTPMH 80

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in the kindlin family; The kindlin family is composed of Kindlin-1, 2 and 3, which are FERM domain-containing adaptor molecules that interact with the cytoplasmic component of integrins and regulate cell-matrix connections. Kindlins belong to the 4.1- ezrin-ridixin-moesin (FERM) domain containing protein family. They contain F1, F2 and F3 subdomains that typify FERM family members, and these subdomains are preceded by an N-terminal F0 subdomain. Both F0 and F1 domains have similar ubiquitin-like folds. This family corresponds to the F1 domain. In addition, a distinctive feature of kindlins is the insertion of a pleckstrin homology (PH) subdomain into the F2 subdomain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609  92 KTLRIQLPDLRFMDAKVDFSVQCFSAVVQLCKDLGIRHPEELSFCRPLcpehlkknykyagvsprqrakdamgpivqnnp 171
Cdd:cd17096     1 KTLRIQLPDLQYLDLRVDFSVKVFNAVVDLCKELGIRHPEELSLLRPP-------------------------------- 48

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 172 yasnistpdgksspavdlnttpvshlngsagsfspisnghstsfdnsfymgsdpsipslasspqtptleakntLIRPKSL 251
Cdd:cd17096    49 -------------------------------------------------------------------------LYRPKSL 55

                         170       180       190
                  ....*....|....*....|....*....|....*
gi 1557985609 252 VERARLNCGWLDSSLSLYEQDVREFDLLLLRFKFY 286
Cdd:cd17096    56 VDKARLNSGWLDSSRSLMEQGVRENDTLLLRFKYY 90

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in kindlin-1 (KIND1); KIND1, also termed Kindlerin, or Kindler syndrome protein, or fermitin family homolog 1 (FERMT1), or Unc-112-related protein 1 (URP1), is an integrin-interacting protein that has been implicated in cell adhesion, proliferation, polarity, and motility. It is essential for maintaining the structure of cell-matrix adhesion, such as focal adhesions and podosomes. KIND1 is expressed primarily in epithelial cells. Loss or mutations of KIND1 gene may cause the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. KIND1 forms a molecular complex with the key transforming growth factor (TGF)-beta/Smad3 signaling components including type I TGFbeta receptor (TbetaRI), Smad3 and Smad anchor for receptor activation (SARA) to control the activation of TGF-beta/Smad3 signaling pathway. KIND1 consists of an atypical FERM domain that is made up of F1, F2 and F3 domains, as well as an N-terminal region, which precedes the FERM domain and has been referred to as the F0 domain. This family corresponds to the F0 domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609  12 SWELKIFVT----DLKVERTLRVKGDLHIGGVMLKLVEDLDVALDWSDHALWWPKKNMWLSRTRTTLDQYGVQADSMLHF 87
Cdd:cd17180     1 SWELSVRVDhqngEEQKEFTLRVSGDLHIGGVMLKLVEQINVAQDWSDYALWWEQKNCWLLKTHWTLDKYGVQADAKLLF 80

                  ....
gi 1557985609  88 TPMH 91
Cdd:cd17180    81 TPQH 84

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in kindlin-2 (KIND2); KIND2, also termed fermitin family homolog 2 (FERMT2), or mitogen-inducible gene 2 protein (MIG-2), or Pleckstrin homology (PH) domain-containing family C member 1, is an adaptor protein that is widely distributed and is particularly abundant in adherent cells. It binds to the integrin beta cytoplasmic tail to promote integrin activation. It promotes carcinogenesis through regulation of cell-cell and cell-extracellular matrix adhesion. KIND2 also plays an important role in cardiac development. KIND2 consists of an atypical FERM domain that is made up of F1, F2 and F3 domains, as well as an N-terminal region, which precedes the FERM domain and has been referred to as the F0 domain. This family corresponds to the F1 domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609  92 KTLRIQLPDLRFMDAKVDFSVQCFSAVVQLCKDLGIRHPEELSFCRplcpehlkknykyagvsprqrakdamgpivqnnp 171
Cdd:cd17184     1 KLLRLQLPNMKYVKVKVNFSDRVFKAVSDICKTFNIRHPEELSLLR---------------------------------- 46

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 172 yasnistpdgksspavdlnttpvshlngsagsfspisnghstsfdnsfymgsdpsipslasSPQTPTLEAK-NTLIRPKS 250
Cdd:cd17184    47 -------------------------------------------------------------KPRDPTKKKKlAKMYKPQS 65

                         170       180       190
                  ....*....|....*....|....*....|....*.
gi 1557985609 251 LVERARLNCGWLDSSLSLYEQDVREFDLLLLRFKFY 286
Cdd:cd17184    66 LLDKAKINQGWLDSSRSLMEQDVKENEALLLRFKYY 101

FERM central domain; This domain is the central structural domain of the FERM domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 464 IRCDaEEQYAKwMAAFHMASKGKTMADASFDSEVKQILDLLSMQHpapapaispnqininpedyiaprfLRKLKSRgQII 543
Cdd:pfam00373  28 LPCS-EEEALL-LAALQLQAEFGDYQPSSHTSEYLSLESFLPKQL------------------------LRKMKSK-ELE 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1557985609 544 QRILEAHANVKDLNSVEAKLNFIKAWQALPEYGISLF 580
Cdd:pfam00373  81 KRVLEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in kindlin-3 (KIND3); KIND3, also termed fermitin family homolog 3 (FERMT3), or MIG2-like protein, or Unc-112-related protein 2, is an adaptor protein that expressed primarily in hematopoietic cells. It plays a central role in cell adhesion in hematopoietic cells, and also promotes integrin activation, clustering and outside-in signaling. KIND3, together with talin-1, contributes essentially to the activation of beta2-integrins in neutrophils. In addition, KIND3 interacts with the ribosome and regulates c-Myc expression required for proliferation of chronic myeloid leukemia cells. Mutations in the KIND3 gene cause leukocyte adhesion deficiency type III (LAD III), which is characterized by high susceptibility to infections, spontaneous and episodic bleedings, and osteopetrosis. KIND3 consists of an atypical FERM domain that is made up of F1, F2 and F3 domains, as well as an N-terminal region, which precedes the FERM domain and has been referred to as the F0 domain. This family corresponds to the F1 domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609  92 KTLRIQLPDLRFMDAKVDFSVQCFSAVVQLCKDLGIRHPEELSFCRPlcpehlkknykyagvsprqrakdamgpivqnnp 171
Cdd:cd17185     1 KPVILSLPNRRSLRIRACFSSPVFRAVAGICRVLSIRHPEELSLLRA--------------------------------- 47

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 172 yasnistpdgksspavdlnttpvshlngsagsfspisnghstsfdnsfymgsdPSIPslasspqtptleakntliRPKSL 251
Cdd:cd17185    48 -----------------------------------------------------PKLY------------------RPSSV 56

                         170       180       190
                  ....*....|....*....|....*....|....*
gi 1557985609 252 VERARLNCGWLDSSLSLYEQDVREFDLLLLRFKFY 286
Cdd:cd17185    57 TDKTQIHSRWLDSSRSLMQQGVQEGDRLWLRFKYY 91

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 1557985609  390 MKPRKFTLKSYKRYFFVFKDTRLAIYKSKDERLGPPAIA-INLKGCEVTPDVNLSQ--RRYGIKLEVPAQEgmvEYLIRC 466
Cdd:smart00233   8 YKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYKPKGsIDLSGCTVREAPDPDSskKPHCFEIKTSDRK---TLLLQA 84

                           90
                   ....*....|....*...
gi 1557985609  467 DAEEQYAKWMAAFHMASK 484
Cdd:smart00233  85 ESEEEREKWVEALRKAIA 102

FERM domain C-lobe; The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1557985609 576 GISLFVVKFDGSKKEEL-LGVASNRLMRMDPNTGDHIKTWRYSTMKAWNVNWEIKKMLV---QFEEEDVQFSCLSADCKV 651
Cdd:cd00836     1 GVEFFPVKDKSKKGSPIiLGVNPEGISVYDELTGQPLVLFPWPNIKKISFSGAKKFTIVvadEDKQSKLLFQTPSRQAKE 80

                          90
                  ....*....|...
gi 1557985609 652 VHEFIGGYIFLSM 664
Cdd:cd00836    81 IWKLIVGYHRFLL 93

TBC1 domain family member 2A pleckstrin homology (PH) domain; TBC1D2A (also called PARIS-1/Prostate antigen recognized and identified by SEREX 1 and ARMUS) contains a PH domain and a TBC-type GTPase catalytic domain. TBC1D2A integrates signaling between Arf6, Rac1, and Rab7 during junction disassembly. Activated Rac1 recruits TBC1D2A to locally inactivate Rab7 via its C-terminal TBC/RabGAP domain and facilitate E-cadherin degradation in lysosomes. The TBC1D2A PH domain mediates localization at cell-cell contacts and coprecipitates with cadherin complexes. 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 1557985609 382 ELADYLRFMKPRKFTLKSYKRYFFVFKDTRLAIYKSKDERLGPPAIAINLKGCEVTPDVNLSQRRYGIK-------LEVP 454
Cdd:cd01265     1 RLCGYLNKLETRGLGLKGWKRRWFVLDESKCQLYYYRSPQDATPLGSIDLSGAAFSYDPEAEPGQFEIHtpgrvhiLKAS 80

                  ....*....
gi 1557985609 455 AQEGMVEYL 463
Cdd:cd01265    81 TRQAMLYWL 89

FERM domain C-lobe/F3 of Talin; Talin (also called filopodin) plays an important role in initiating actin filament growth in motile cell protrusions. It is responsible for linking the cytoplasmic domains of integrins to the actin-based cytoskeleton, and is involved in vinculin, integrin and actin interactions. At the leading edge of motile cells, talin colocalises with the hyaluronan receptor layilin in transient adhesions, some of which become more stable focal adhesions (FA). During this maturation process, layilin is replaced with integrins, where localized production of PI(4,5)P(2) by type 1 phosphatidyl inositol phosphate kinase type 1gamma (PIPK1gamma) is thought to play a role in FA assembly. Talins are composed of a N-terminal region FERM domain which us made up of 3 subdomains (N, alpha-, and C-lobe; or- A-lobe, B-lobe, and C-lobe; or F1, F2, and F3) connected by short linkers, a talin rod which binds vinculin, and a conserved C-terminal region with actin- and integrin-binding sites. There are 2 additional actin-binding domains, one in the talin rod and the other in the FERM domain. Both the F2 and F3 FERM subdomains contribute to F-actin binding. Subdomain F3 of the FERM domain contains overlapping binding sites for integrin cytoplasmic domains and for the type 1 gamma isoform of PIP-kinase (phosphatidylinositol 4-phosphate 5-kinase). The FERM domain has a cloverleaf tripart structure . F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1557985609 576 GISLFVVKFD--GSKKEE--LLGVASNRLMRMDPNTGDHIKTWRYSTMKAW 622
Cdd:cd10569     1 GVTFFLVKEKmkGKNKLVprLLGITKESVLRLDEETKEVLKVWPLTTIKRW 51

ARHGAP21 and related proteins pleckstrin homology (PH) domain; ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with a RhoGAP domain. These proteins functions as a GTPase-activating protein (GAP) for RHOA and CDC42. ARHGAP21 controls the Arp2/3 complex and F-actin dynamics at the Golgi complex by regulating the activity of the small GTPase Cdc42. It is recruited to the Golgi by to GTPase, ARF1, through its PH domain and its helical motif. It is also required for CTNNA1 recruitment to adherens junctions. ARHGAP21 and it related proteins all contains a PH domain and a RhoGAP domain. Some of the members have additional N-terminal domains including PDZ, SH3, and SPEC. The ARHGAP21 PH domain interacts with the GTPbound forms of both ARF1 and ARF6 ARF-binding domain/ArfBD. The members here include: ARHGAP15, ARHGAP21, and ARHGAP23. 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 1557985609 391 KPRKFTLKSYKRYFFVFKDTRLAIYKSKDERLGPPAIA------INLKGCevTPDVNLS--QRRYGIKLEVPAQegmVEY 462
Cdd:cd01253    15 KGKRVSDRSWKQAWAVLRGHSLYLYKDKREQTPALSIElgseqrISIRGC--IVDIAYSytKRKHVFRLTTSDF---SEY 89

                          90
                  ....*....|....*...
gi 1557985609 463 LIRCDAEEQYAKWMAAFH 480
Cdd:cd01253    90 LFQAEDRDDMLGWIKAIQ 107