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 24657225 401 PELSDYLKFLKPQRFTLKGYKRYFFTYRDLHLHLYKSQDESRrGAPTISINLKGCEVTPDVNLAQGKFAIRLEVPSEirn 480
Cdd:cd01237   1 PELADYLKYFKPKKFTLKGYKRYWFVFKDTHLSYYKSKEESN-GAPIQQINLKGCEVTPDVNVSQQKFCIKLLVPSP--- 76

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 24657225 481 GPNSEVWVRCDNEEQYAKWMAACRLAAKGRSLADSSYDSEVSSIRSLLQ 529
Cdd:cd01237  77 EGMSEVWLRCDNEDQYAKWMAACRLASKGKTMADSSYDSEVSSILAFLS 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 24657225   8 TWNLRILITDLQVEKTLRVKGDQHIGGVMLNLVDP-ELPKDWSDHALWWPAKNIWLTRTRSTLDQAGVQSDSFLHFTPMH 86
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 24657225   490 CDnEEQYAKwMAACRLAAKGRSLADSSYDSEVSSIRSLLQMQkpaqgapltvnprsvepmdylspkMMRKLSSKAV-QRI 568
Cdd:pfam00373  30 CS-EEEALL-LAALQLQAEFGDYQPSSHTSEYLSLESFLPKQ------------------------LLRKMKSKELeKRV 83

                          90       100       110
                  ....*....|....*....|....*....|....
gi 24657225   569 LEAHANVRQLSLMDAKMKYIQAWQSLPDFGVTLF 602
Cdd:pfam00373  84 LEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 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 24657225 401 PELSDYLKFLKPQRFTLKGYKRYFFTYRDLHLHLYKSQDESRrGAPTISINLKGCEVTPDVNLAQGKFAIRLEVPSEirn 480
Cdd:cd01237   1 PELADYLKYFKPKKFTLKGYKRYWFVFKDTHLSYYKSKEESN-GAPIQQINLKGCEVTPDVNVSQQKFCIKLLVPSP--- 76

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 24657225 481 GPNSEVWVRCDNEEQYAKWMAACRLAAKGRSLADSSYDSEVSSIRSLLQ 529
Cdd:cd01237  77 EGMSEVWLRCDNEDQYAKWMAACRLASKGKTMADSSYDSEVSSILAFLS 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 24657225   8 TWNLRILITDLQVEKTLRVKGDQHIGGVMLNLVDP-ELPKDWSDHALWWPAKNIWLTRTRSTLDQAGVQSDSFLHFTPMH 86
Cdd:cd17095   1 SWELSITVTDLQIERKLRVTGDLHIGGVMLKLVETlGVAQDWSDHALWWPQKRVWLLKTRSTLDQYGVQADAELHFTPMH 80

Kindlin-2 N-terminal domain; This is the N-terminal domain (K2-N) of Kindlin-2 protein present in Homo sapiens. Kindlin-2 is a regulator for heterodimeric integrin adhesion receptors promotes integrin activation. Activation depends on binding of the N-terminal domain to the integrin beta cytoplasmic tail (CT), which disrupts the receptors association with alpha-CT and triggers the conformational transitions in the receptor. K2-N contains a conserved positively charged surface that binds to membrane enriched with negatively charged phosphatidylinositol-(4,5)-bisphosphate (PIP2). K2-N is also very similar to the homologous kindlin-1 F0.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24657225     4 VGENTWNLRILITDL----QVEKTLRVKGDQHIGGVMLNLVDP-ELPKDWSDHALWWPAKNIWLTRTRSTLDQAGVQSDS 78
Cdd:pfam18124   1 YADGSWELKITVTDMsikkEVEIPVRVTGDLHIGGVMLKLVESlDITKDWSDHALWWPQACKWLDKTGQTLDKYGVQADA 80

                  ....*....
gi 24657225    79 FLHFTPMHK 87
Cdd:pfam18124  81 VLLYTPKHK 89

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 24657225    274 WLDSSLSIMEQGVR-EYDTLCLRFKYFTFFDLNPKYDQVRINQLYEQAKWSILNEELEPTEEETLMFAALQFQV---NHQ 349
Cdd:smart00295  55 WLDPAKTLLDQDVKsEPLTLYFRVKFYPPDPNQLKEDPTRLNLLYLQVRNDILEGRLPCPEEEALLLAALALQAefgDYD 134

                           90
                   ....*....|....
gi 24657225    350 TDLHPPGIDSGIDT 363
Cdd:smart00295 135 EELHDLRGELSLKR 148

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24657225   401 PELSDYLKFLKPQRFtlKGYKRYFFTYRDLHLHLYKSQDESRRGAPTISINLKGCEVTPDVNLAQGK----FAIRLevps 476
Cdd:pfam00169   1 VVKEGWLLKKGGGKK--KSWKKRYFVLFDGSLLYYKDDKSGKSKEPKGSISLSGCEVVEVVASDSPKrkfcFELRT---- 74

                          90       100       110
                  ....*....|....*....|....*....|..
gi 24657225   477 eIRNGPNSEVWVRCDNEEQYAKWMAACRLAAK 508
Cdd:pfam00169  75 -GERTGKRTYLLQAESEEERKDWIKAIQSAIR 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
                   ....*....|....*....|....*....|....*....|....*....|....
gi 24657225    550 DYLSPKMMRKLSSKAV-QRILEAHANVRQLSLMDAKMKYIQAWQSLPDFGVTLF 602
Cdd:smart00295 148 RFLPKQLLDSRKLKEWrERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

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 24657225 401 PELSDYLKFLKPQRFTLKGYKRYFFTYRDLHLHLYKSQDESRrGAPTISINLKGCEVTPDVNLAQGKFAIRLEVPSEirn 480
Cdd:cd01237   1 PELADYLKYFKPKKFTLKGYKRYWFVFKDTHLSYYKSKEESN-GAPIQQINLKGCEVTPDVNVSQQKFCIKLLVPSP--- 76

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 24657225 481 GPNSEVWVRCDNEEQYAKWMAACRLAAKGRSLADSSYDSEVSSIRSLLQ 529
Cdd:cd01237  77 EGMSEVWLRCDNEDQYAKWMAACRLASKGKTMADSSYDSEVSSILAFLS 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 24657225   8 TWNLRILITDLQVEKTLRVKGDQHIGGVMLNLVDP-ELPKDWSDHALWWPAKNIWLTRTRSTLDQAGVQSDSFLHFTPMH 86
Cdd:cd17095   1 SWELSITVTDLQIERKLRVTGDLHIGGVMLKLVETlGVAQDWSDHALWWPQKRVWLLKTRSTLDQYGVQADAELHFTPMH 80

Kindlin-2 N-terminal domain; This is the N-terminal domain (K2-N) of Kindlin-2 protein present in Homo sapiens. Kindlin-2 is a regulator for heterodimeric integrin adhesion receptors promotes integrin activation. Activation depends on binding of the N-terminal domain to the integrin beta cytoplasmic tail (CT), which disrupts the receptors association with alpha-CT and triggers the conformational transitions in the receptor. K2-N contains a conserved positively charged surface that binds to membrane enriched with negatively charged phosphatidylinositol-(4,5)-bisphosphate (PIP2). K2-N is also very similar to the homologous kindlin-1 F0.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24657225     4 VGENTWNLRILITDL----QVEKTLRVKGDQHIGGVMLNLVDP-ELPKDWSDHALWWPAKNIWLTRTRSTLDQAGVQSDS 78
Cdd:pfam18124   1 YADGSWELKITVTDMsikkEVEIPVRVTGDLHIGGVMLKLVESlDITKDWSDHALWWPQACKWLDKTGQTLDKYGVQADA 80

                  ....*....
gi 24657225    79 FLHFTPMHK 87
Cdd:pfam18124  81 VLLYTPKHK 89

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 24657225   8 TWNLRILIT----DLQVEKTLRVKGDQHIGGVMLNLVDP-ELPKDWSDHALWWPAKNIWLTRTRSTLDQAGVQSDSFLHF 82
Cdd:cd17180   1 SWELSVRVDhqngEEQKEFTLRVSGDLHIGGVMLKLVEQiNVAQDWSDYALWWEQKNCWLLKTHWTLDKYGVQADAKLLF 80

                ....
gi 24657225  83 TPMH 86
Cdd:cd17180  81 TPQH 84

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24657225   490 CDnEEQYAKwMAACRLAAKGRSLADSSYDSEVSSIRSLLQMQkpaqgapltvnprsvepmdylspkMMRKLSSKAV-QRI 568
Cdd:pfam00373  30 CS-EEEALL-LAALQLQAEFGDYQPSSHTSEYLSLESFLPKQ------------------------LLRKMKSKELeKRV 83

                          90       100       110
                  ....*....|....*....|....*....|....
gi 24657225   569 LEAHANVRQLSLMDAKMKYIQAWQSLPDFGVTLF 602
Cdd:pfam00373  84 LEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 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 F1 domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 24657225 256 ARLVRPKSRVEKARLNVGWLDSSLSIMEQGVREYDTLCLRFKYF 299
Cdd:cd17183  50 AKMYQPRTLLDKAKLNAGWLDSSRSLMEQGIQEDDQLLLRFKYY 93

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 24657225    401 PELSDYLKFLKPQRFtlKGYKRYFFTYRDLHLHLYKSQDESRRGAPTISINLKGCEVTPDVN--LAQGKFAIrlevpsEI 478
Cdd:smart00233   1 VIKEGWLYKKSGGGK--KSWKKRYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCTVREAPDpdSSKKPHCF------EI 72

                           90       100       110
                   ....*....|....*....|....*....|
gi 24657225    479 RNGPNSEVWVRCDNEEQYAKWMAACRLAAK 508
Cdd:smart00233  73 KTSDRKTLLLQAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24657225   401 PELSDYLKFLKPQRFtlKGYKRYFFTYRDLHLHLYKSQDESRRGAPTISINLKGCEVTPDVNLAQGK----FAIRLevps 476
Cdd:pfam00169   1 VVKEGWLLKKGGGKK--KSWKKRYFVLFDGSLLYYKDDKSGKSKEPKGSISLSGCEVVEVVASDSPKrkfcFELRT---- 74

                          90       100       110
                  ....*....|....*....|....*....|..
gi 24657225   477 eIRNGPNSEVWVRCDNEEQYAKWMAACRLAAK 508
Cdd:pfam00169  75 -GERTGKRTYLLQAESEEERKDWIKAIQSAIR 105

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 24657225 409 FLKPQRFTLKGYKRYFFTYRDLHLHLYKSQDEsRRGAPTISINLKG-CEVTPDVNLAQgKFAIRLEVPSEirngpnSEVW 487
Cdd:cd00821   5 LLKRGGGGLKSWKKRWFVLFEGVLLYYKSKKD-SSYKPKGSIPLSGiLEVEEVSPKER-PHCFELVTPDG------RTYY 76

                        90
                ....*....|....*.
gi 24657225 488 VRCDNEEQYAKWMAAC 503
Cdd:cd00821  77 LQADSEEERQEWLKAL 92

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
                   ....*....|....*....|....*....|....*....|....*....|....
gi 24657225    550 DYLSPKMMRKLSSKAV-QRILEAHANVRQLSLMDAKMKYIQAWQSLPDFGVTLF 602
Cdd:smart00295 148 RFLPKQLLDSRKLKEWrERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

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        60        70        80
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gi 24657225 598 GVTLFIIKFD--GHKKEE--LLGVANNRIMRMDLNTGDHIKTWRYNTMKAWNVnwGIKCMMIQLQD-ENIVFSVQSADCK 672
Cdd:cd10569   1 GVTFFLVKEKmkGKNKLVprLLGITKESVLRLDEETKEVLKVWPLTTIKRWAA--SPKSFTLDFGDySENYYSVQTTEGE 78

                        90
                ....*....|
gi 24657225 673 VVHEFIGGYI 682
Cdd:cd10569  79 QISQLISGYI 88

Yeast oxysterol binding protein homologs 1 and 2 Pleckstrin homology (PH) domain; Yeast Osh1p is proposed to function in postsynthetic sterol regulation, piecemeal microautophagy of the nucleus, and cell polarity establishment. Yeast Osh2p is proposed to function in sterol metabolism and cell polarity establishment. Both Osh1p and Osh2p contain 3 N-terminal ankyrin repeats, a PH domain, a FFAT motif (two phenylalanines in an acidic tract), and a C-terminal OSBP-related domain. OSBP andOsh1p PH domains specifically localize to the Golgi apparatus in a PtdIns4P-dependent manner. Oxysterol binding proteins are a multigene family that is conserved in yeast, flies, worms, mammals and plants. In general OSBPs and ORPs have been found to be involved in the transport and metabolism of cholesterol and related lipids in eukaryotes. They all contain a C-terminal oxysterol binding domain, and most contain an N-terminal PH domain. OSBP PH domains bind to membrane phosphoinositides and thus likely play an important role in intracellular targeting. They are members of the oxysterol binding protein (OSBP) family which includes OSBP, OSBP-related proteins (ORP), Goodpasture antigen binding protein (GPBP), and Four phosphate adaptor protein 1 (FAPP1). They have a wide range of purported functions including sterol transport, cell cycle control, pollen development and vessicle transport from Golgi recognize both PI lipids and ARF proteins. 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.

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gi 24657225 401 PELSDYLKflKPQRFTlKGYKRYFFTYRDLHLHLYKSQDESRRgAPTISINLKGCEVTPDvnlAQGKfaIRLEVPSEIRN 480
Cdd:cd13292   2 PTMKGYLK--KWTNYA-KGYKTRWFVLEDGVLSYYRHQDDEGS-ACRGSINMKNARLVSD---PSEK--LRFEVSSKTSG 72

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gi 24657225 481 GPNsevW-VRCDNEEQYAKWMAA 502
Cdd:cd13292  73 SPK---WyLKANHPVEAARWIQA 92