Talin, middle domain; Members of this family adopt a structure consisting of five alpha helices that fold into a bundle. They contain a Vinculin binding site (VBS) composed of a hydrophobic surface spanning five turns of helix four. Activation of the VBS causes subsequent recruitment of Vinculin, which enables maturation of small integrin/talin complexes into more stable adhesions. Formation of the complex between VBS and Vinculin requires prior unfolding of this middle domain: once released from the talin hydrophobic core, the VBS helix is then available to induce the 'bundle conversion' conformational change within the vinculin head domain thereby displacing the intramolecular interaction with the vinculin tail, allowing vinculin to bind actin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073   510 PQRALLGYISAGQDVLIRADEELRTKAPIQELGSDLRSIEWRENTLDTSKQAVSSHVATMSAATAQII--TASHPDEVDT 587
Cdd:pfam09141    1 PQRALLGTISAGQEAIQAAEAELDTPAQLPPLGSDAASLQWRENTLDVSKQNVSSQLAAMNAATAQVVtlTSGPPDEIDY 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073   588 EAISASVSQIAQTIPEVTKEVRLIAALMENDTSGDQLLEAARNLCSAFSDLLKAAEPESKEPPQHLINAASRVGEATTHV 667
Cdd:pfam09141   81 TAVGAAITTISSNLPEMSKGVRMLAALMDDEDSGDKLLDAARKLCGAFSDLLKAAQPESKEPRQNLLNAASRVGEASQQL 160

                   .
gi 442631073   668 L 668
Cdd:pfam09141  161 L 161

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073  318 GVTFFLVKEKMNGKNKLVPRLLGVTKDSVLRLDEHTKEILISWPLTTVRRWGASPNTFTLDFGDYANQYYSVQTTEAEQI 397
Cdd:cd10569     1 GVTFFLVKEKMKGKNKLVPRLLGITKESVLRLDEETKEVLKVWPLTTIKRWAASPKSFTLDFGDYSENYYSVQTTEGEQI 80

                          90
                  ....*....|..
gi 442631073  398 VQLIAGYIDIIL 409
Cdd:cd10569    81 SQLISGYIDIIL 92

I/LWEQ domain; I/LWEQ domains bind to actin. It has been shown that the I/LWEQ domains from mouse talin and yeast Sla2p interact with F-actin. I/LWEQ domains can be placed into four major groups based on sequence similarity: (1) Metazoan talin; (2) Dictyostelium TalA/TalB and SLA110; (3) metazoan Hip1p; and (4) yeast Sla2p. The domain has four conserved blocks, the name of the domain is derived from the initial conserved amino acid of each of the four blocks.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073  2392 DDGQWSEGLISAARLVAAATHSLVEAAQNLVRGVGTEEMLISTAKQVAASTAQLLIACKVKSNPNSEAGRRLQAAGNAVI 2471
Cdd:pfam01608    1 KNNRWTEGLISAAKAVAAATNLLVEAADGVVQGQGSEEELIVAAKEVAASTAQLVAASRVKADPNSKTQQRLEAASKAVT 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 442631073  2472 KSTDNLVHSAQQGL----EAEEEHSLKINTSMVDGMAQEINARSAVLRKEKELEEARQLLKNVRHA 2533
Cdd:pfam01608   81 DATKNLVAAVKSAAelqeEEIEEEMDFSKLSLHQAKRQEMEAQVEILKLEKELEEARKKLAEIRKA 146

N-terminal or F0 domain of Talin-head FERM; FERM_f0 forms a stable globular structure. The fold is an ubiquitin-like fold joined to the f1 domain in a novel fixed orientation by an extensive charged interface. It is required for maximal integrin-activation, by interacting with other FA components, No binding partner has yet been found for it.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073     4 LSLRIQLEGGRVTKTIQFQPNTTVFDACKVIRDKFAEAvQGQPSEYGLFISDEQNQQGVWLEPGRTLGYYILHNQDTLEY 83
Cdd:pfam16511    1 LSLKISIVGSNVTKTMQFDPSTTVYDACRLIREKIPEG-GLNASEYGLFLADEDPKKGRWLEPGRTLEYYDLRNGDELEY 79

                   ..
gi 442631073    84 RR 85
Cdd:pfam16511   80 KK 81

Vinculin family;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073   874 LLSAAKQLADATAKLVEAARLCSSNPHDSDNQ-----------NALRKAAEELREITTT----AANTPAMKRGL------ 932
Cdd:pfam01044  431 IRMAAAQVESLTPQVINAARILLHNPGSKAAQenmetfknqweDQVRRLTEAVDDITDTddflAVSEEHILEDVnkcvma 510

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073   933 -----IQRLEFCSKQAASAATQCISAAQNAVQHSQDHQTKETLLQDCKRVADTIPRLVTSLKTTRAQPDDPNAQLNLIEA 1007
Cdd:pfam01044  511 iqnadPQTLVATAGSIAGRANRVLLVAKAEMDNSEDPVYTERVKEAVDILSNTIPPMFAEAKEVAVNALDPGAAKSWEEN 590

                          170       180
                   ....*....|....*....|....*...
gi 442631073  1008 AEQFIEpalqvskSSRALQPTVTDIPSA 1035
Cdd:pfam01044  591 NYEFLD-------AVRLVYDAVRPIRQA 611

Talin, middle domain; Members of this family adopt a structure consisting of five alpha helices that fold into a bundle. They contain a Vinculin binding site (VBS) composed of a hydrophobic surface spanning five turns of helix four. Activation of the VBS causes subsequent recruitment of Vinculin, which enables maturation of small integrin/talin complexes into more stable adhesions. Formation of the complex between VBS and Vinculin requires prior unfolding of this middle domain: once released from the talin hydrophobic core, the VBS helix is then available to induce the 'bundle conversion' conformational change within the vinculin head domain thereby displacing the intramolecular interaction with the vinculin tail, allowing vinculin to bind actin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073   510 PQRALLGYISAGQDVLIRADEELRTKAPIQELGSDLRSIEWRENTLDTSKQAVSSHVATMSAATAQII--TASHPDEVDT 587
Cdd:pfam09141    1 PQRALLGTISAGQEAIQAAEAELDTPAQLPPLGSDAASLQWRENTLDVSKQNVSSQLAAMNAATAQVVtlTSGPPDEIDY 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073   588 EAISASVSQIAQTIPEVTKEVRLIAALMENDTSGDQLLEAARNLCSAFSDLLKAAEPESKEPPQHLINAASRVGEATTHV 667
Cdd:pfam09141   81 TAVGAAITTISSNLPEMSKGVRMLAALMDDEDSGDKLLDAARKLCGAFSDLLKAAQPESKEPRQNLLNAASRVGEASQQL 160

                   .
gi 442631073   668 L 668
Cdd:pfam09141  161 L 161

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073  318 GVTFFLVKEKMNGKNKLVPRLLGVTKDSVLRLDEHTKEILISWPLTTVRRWGASPNTFTLDFGDYANQYYSVQTTEAEQI 397
Cdd:cd10569     1 GVTFFLVKEKMKGKNKLVPRLLGITKESVLRLDEETKEVLKVWPLTTIKRWAASPKSFTLDFGDYSENYYSVQTTEGEQI 80

                          90
                  ....*....|..
gi 442631073  398 VQLIAGYIDIIL 409
Cdd:cd10569    81 SQLISGYIDIIL 92

I/LWEQ domain; I/LWEQ domains bind to actin. It has been shown that the I/LWEQ domains from mouse talin and yeast Sla2p interact with F-actin. I/LWEQ domains can be placed into four major groups based on sequence similarity: (1) Metazoan talin; (2) Dictyostelium TalA/TalB and SLA110; (3) metazoan Hip1p; and (4) yeast Sla2p. The domain has four conserved blocks, the name of the domain is derived from the initial conserved amino acid of each of the four blocks.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073  2392 DDGQWSEGLISAARLVAAATHSLVEAAQNLVRGVGTEEMLISTAKQVAASTAQLLIACKVKSNPNSEAGRRLQAAGNAVI 2471
Cdd:pfam01608    1 KNNRWTEGLISAAKAVAAATNLLVEAADGVVQGQGSEEELIVAAKEVAASTAQLVAASRVKADPNSKTQQRLEAASKAVT 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 442631073  2472 KSTDNLVHSAQQGL----EAEEEHSLKINTSMVDGMAQEINARSAVLRKEKELEEARQLLKNVRHA 2533
Cdd:pfam01608   81 DATKNLVAAVKSAAelqeEEIEEEMDFSKLSLHQAKRQEMEAQVEILKLEKELEEARKKLAEIRKA 146

Vinculin Binding Site; Vinculin binding sites are predominantly found in talin and talin-like molecules, enabling binding of vinculin to talin, stabilising integrin-mediated cell-matrix junctions. Talin, in turn, links integrins to the actin cytoskeleton. The consensus sequence for Vinculin binding sites is LxxAAxxVAxxVxxLIxxA, with a secondary structure prediction of four amphipathic helices. The hydrophobic residues that define the VBS are themselves 'masked' and are buried in the core of a series of helical bundles that make up the talin rod.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073  1859 TFVDYQTRMVARAKEIASLANEMNAKSSVEPSALPQLAVDMTQNYQQLTQDSVGASTTTSSPDVAMRIRTTVIDLGRSVS 1938
Cdd:pfam08913    1 TFVDYQTTMVRYAKAIAVTAQEMNTKSVTSPEELGQLASQMTSDYGQLAQQGIGASATAEPEEIGFQIRTRVQDLGHGCI 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 442631073  1939 SMIQSSAG-GARPNDAGAQKEIARSAREVSEKVAQVLAALQAGSR 1982
Cdd:pfam08913   81 VLVQKAGAlQISPTDSYTKRELIECARAVSEKVSQVLAALQAGNR 125

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in Talin and similar proteins; Talin is a cytoskeletal protein that activates integrins and couples them to cytoskeletal actin. Talin consists of an N-terminal head and a C-terminal rod. The talin head harbors a FERM (Band 4.1, ezrin, radixin, moesin) domain made up of F1, F2 and F3 domains, as well as an N-terminal region that precedes the FERM domain and has been referred to as the F0 domain. Both F0 and F1 domains have similar ubiquitin-like folds. This family corresponds to the F0 domain that is joined to the F1 domain in a novel fixed orientation by an extensive charged interface. It is required for maximal integrin-activation, by interacting with other FA components; no binding partner has yet been found for it.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073    4 LSLRIQLEGGRVTKTIQFQPNTTVFDACKVIRDKFAEAVQGQPSEYGLFISDEQNQQGVWLEPGRTLGYYILHNQDTLEY 83
Cdd:cd17089     1 LSLKIHIVKSGIVKTMQFDPSMTVYDACRLIREKIPEAAQGQASDYGLFLPDEDPKKGRWLEPDRTLEYYDLRNGDELEY 80

                  ...
gi 442631073   84 RRK 86
Cdd:cd17089    81 KKK 83

FERM domain B-lobe; The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The 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, the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the pleckstrin homology (PH) and phosphotyrosine binding (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 442631073  219 QLNLLYVQARDAILDGTHPVTQDKACEFAGIQVHIQFGPHNEAKHKTGFLDLKDFLPQSYVRTKG---IEKKIFSEHRKH 295
Cdd:cd14473     1 TRYLLYLQVKRDILEGRLPCSEETAALLAALALQAEYGDYDPSEHKPKYLSLKRFLPKQLLKQRKpeeWEKRIVELHKKL 80

                          90
                  ....*....|....*....
gi 442631073  296 VDLSEIDAKVLYTKTAREL 314
Cdd:cd14473    81 RGLSPAEAKLKYLKIARKL 99

Phosphotyrosine-binding domain (IRS1-like);

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*....
gi 442631073    346 VLRLDEHTKEILISWPLTTVRRWGASPNTFTLDFG---DYANQYYSVQTTEAEQIVQLI 401
Cdd:smart00310   32 VLWRGLNPRVELVVWPLLSLRRYGRDKVFFFFEAGrrcVSGPGEFTFQTVVAQEIFQLV 90

FERM N-terminal domain; This domain is the N-terminal ubiquitin-like structural domain of the FERM domain.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 442631073    92 VRMLDGAVKTILVDDSQPVSQLMVVICTKIGITNHEEYGLVREDNEAQNENLPDNK 147
Cdd:pfam09379    1 VRLLDGTVLEFDVQPKATGQVLLDQVCNHLNLKEKDYFGLQFLDDNGEHRWLDLSK 56

Vinculin family;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073   874 LLSAAKQLADATAKLVEAARLCSSNPHDSDNQ-----------NALRKAAEELREITTT----AANTPAMKRGL------ 932
Cdd:pfam01044  431 IRMAAAQVESLTPQVINAARILLHNPGSKAAQenmetfknqweDQVRRLTEAVDDITDTddflAVSEEHILEDVnkcvma 510

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073   933 -----IQRLEFCSKQAASAATQCISAAQNAVQHSQDHQTKETLLQDCKRVADTIPRLVTSLKTTRAQPDDPNAQLNLIEA 1007
Cdd:pfam01044  511 iqnadPQTLVATAGSIAGRANRVLLVAKAEMDNSEDPVYTERVKEAVDILSNTIPPMFAEAKEVAVNALDPGAAKSWEEN 590

                          170       180
                   ....*....|....*....|....*...
gi 442631073  1008 AEQFIEpalqvskSSRALQPTVTDIPSA 1035
Cdd:pfam01044  591 NYEFLD-------AVRLVYDAVRPIRQA 611

Talin, middle domain; Members of this family adopt a structure consisting of five alpha helices that fold into a bundle. They contain a Vinculin binding site (VBS) composed of a hydrophobic surface spanning five turns of helix four. Activation of the VBS causes subsequent recruitment of Vinculin, which enables maturation of small integrin/talin complexes into more stable adhesions. Formation of the complex between VBS and Vinculin requires prior unfolding of this middle domain: once released from the talin hydrophobic core, the VBS helix is then available to induce the 'bundle conversion' conformational change within the vinculin head domain thereby displacing the intramolecular interaction with the vinculin tail, allowing vinculin to bind actin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073   510 PQRALLGYISAGQDVLIRADEELRTKAPIQELGSDLRSIEWRENTLDTSKQAVSSHVATMSAATAQII--TASHPDEVDT 587
Cdd:pfam09141    1 PQRALLGTISAGQEAIQAAEAELDTPAQLPPLGSDAASLQWRENTLDVSKQNVSSQLAAMNAATAQVVtlTSGPPDEIDY 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073   588 EAISASVSQIAQTIPEVTKEVRLIAALMENDTSGDQLLEAARNLCSAFSDLLKAAEPESKEPPQHLINAASRVGEATTHV 667
Cdd:pfam09141   81 TAVGAAITTISSNLPEMSKGVRMLAALMDDEDSGDKLLDAARKLCGAFSDLLKAAQPESKEPRQNLLNAASRVGEASQQL 160

                   .
gi 442631073   668 L 668
Cdd:pfam09141  161 L 161

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073  318 GVTFFLVKEKMNGKNKLVPRLLGVTKDSVLRLDEHTKEILISWPLTTVRRWGASPNTFTLDFGDYANQYYSVQTTEAEQI 397
Cdd:cd10569     1 GVTFFLVKEKMKGKNKLVPRLLGITKESVLRLDEETKEVLKVWPLTTIKRWAASPKSFTLDFGDYSENYYSVQTTEGEQI 80

                          90
                  ....*....|..
gi 442631073  398 VQLIAGYIDIIL 409
Cdd:cd10569    81 SQLISGYIDIIL 92

I/LWEQ domain; I/LWEQ domains bind to actin. It has been shown that the I/LWEQ domains from mouse talin and yeast Sla2p interact with F-actin. I/LWEQ domains can be placed into four major groups based on sequence similarity: (1) Metazoan talin; (2) Dictyostelium TalA/TalB and SLA110; (3) metazoan Hip1p; and (4) yeast Sla2p. The domain has four conserved blocks, the name of the domain is derived from the initial conserved amino acid of each of the four blocks.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073  2392 DDGQWSEGLISAARLVAAATHSLVEAAQNLVRGVGTEEMLISTAKQVAASTAQLLIACKVKSNPNSEAGRRLQAAGNAVI 2471
Cdd:pfam01608    1 KNNRWTEGLISAAKAVAAATNLLVEAADGVVQGQGSEEELIVAAKEVAASTAQLVAASRVKADPNSKTQQRLEAASKAVT 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 442631073  2472 KSTDNLVHSAQQGL----EAEEEHSLKINTSMVDGMAQEINARSAVLRKEKELEEARQLLKNVRHA 2533
Cdd:pfam01608   81 DATKNLVAAVKSAAelqeEEIEEEMDFSKLSLHQAKRQEMEAQVEILKLEKELEEARKKLAEIRKA 146

Vinculin Binding Site; Vinculin binding sites are predominantly found in talin and talin-like molecules, enabling binding of vinculin to talin, stabilising integrin-mediated cell-matrix junctions. Talin, in turn, links integrins to the actin cytoskeleton. The consensus sequence for Vinculin binding sites is LxxAAxxVAxxVxxLIxxA, with a secondary structure prediction of four amphipathic helices. The hydrophobic residues that define the VBS are themselves 'masked' and are buried in the core of a series of helical bundles that make up the talin rod.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073  1859 TFVDYQTRMVARAKEIASLANEMNAKSSVEPSALPQLAVDMTQNYQQLTQDSVGASTTTSSPDVAMRIRTTVIDLGRSVS 1938
Cdd:pfam08913    1 TFVDYQTTMVRYAKAIAVTAQEMNTKSVTSPEELGQLASQMTSDYGQLAQQGIGASATAEPEEIGFQIRTRVQDLGHGCI 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 442631073  1939 SMIQSSAG-GARPNDAGAQKEIARSAREVSEKVAQVLAALQAGSR 1982
Cdd:pfam08913   81 VLVQKAGAlQISPTDSYTKRELIECARAVSEKVSQVLAALQAGNR 125

N-terminal or F0 domain of Talin-head FERM; FERM_f0 forms a stable globular structure. The fold is an ubiquitin-like fold joined to the f1 domain in a novel fixed orientation by an extensive charged interface. It is required for maximal integrin-activation, by interacting with other FA components, No binding partner has yet been found for it.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073     4 LSLRIQLEGGRVTKTIQFQPNTTVFDACKVIRDKFAEAvQGQPSEYGLFISDEQNQQGVWLEPGRTLGYYILHNQDTLEY 83
Cdd:pfam16511    1 LSLKISIVGSNVTKTMQFDPSTTVYDACRLIREKIPEG-GLNASEYGLFLADEDPKKGRWLEPGRTLEYYDLRNGDELEY 79

                   ..
gi 442631073    84 RR 85
Cdd:pfam16511   80 KK 81

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in Talin and similar proteins; Talin is a cytoskeletal protein that activates integrins and couples them to cytoskeletal actin. Talin consists of an N-terminal head and a C-terminal rod. The talin head harbors a FERM (Band 4.1, ezrin, radixin, moesin) domain made up of F1, F2 and F3 domains, as well as an N-terminal region that precedes the FERM domain and has been referred to as the F0 domain. Both F0 and F1 domains have similar ubiquitin-like folds. This family corresponds to the F0 domain that is joined to the F1 domain in a novel fixed orientation by an extensive charged interface. It is required for maximal integrin-activation, by interacting with other FA components; no binding partner has yet been found for it.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073    4 LSLRIQLEGGRVTKTIQFQPNTTVFDACKVIRDKFAEAVQGQPSEYGLFISDEQNQQGVWLEPGRTLGYYILHNQDTLEY 83
Cdd:cd17089     1 LSLKIHIVKSGIVKTMQFDPSMTVYDACRLIREKIPEAAQGQASDYGLFLPDEDPKKGRWLEPDRTLEYYDLRNGDELEY 80

                  ...
gi 442631073   84 RRK 86
Cdd:cd17089    81 KKK 83

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in Talin-1 (TLN1); TLN1 is a cytoskeletal protein that plays a pivotal role in regulating the activity of the integrin family of cell adhesion proteins by coupling them to F-actin. It functions as a focal adhesion protein involved in the attachment of the bacterium. It binds to multiple adhesion molecules, including integrins, vinculin, focal adhesion kinase (FAK), and actin. TLN1 also plays an essential role in integrin activation. TLN1 interacts with the hepatitis B virus (HBV) accessory protein X (HBx), which induces the degradation of TLN1. It also acts as an adaptor protein that regulates leukocyte function-associated antigen-1 (LFA-1) affinity. In addition, TLN1 is required for myoblast fusion, sarcomere assembly and the maintenance of myotendinous junctions. TLN1 consists of an N-terminal head and a C-terminal rod. The talin head harbors a FERM (Band 4.1, ezrin, radixin, moesin) domain made up of F1, F2 and F3 domains, as well as an N-terminal region that precedes the FERM domain and has been referred to as the F0 domain. Both F0 and F1 domains have similar ubiquitin-like folds. This family corresponds to the F0 domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442631073    4 LSLRIQLegGRVTKTIQFQPNTTVFDACKVIRDKFAEAVQGQPSEYGLFISDEQNQQGVWLEPGRTLGYYILHNQDTLEY 83
Cdd:cd17171     3 LSLKISI--GNVVKTMQFEPSTMVYDACRMIRERVPEAQAGQPNDFGLFLSDDDPKKGIWLEAGKALDYYMLRNGDTMEY 80

                  ...
gi 442631073   84 RRK 86
Cdd:cd17171    81 RKK 83

FERM domain B-lobe; The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The 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, the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the pleckstrin homology (PH) and phosphotyrosine binding (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 442631073  219 QLNLLYVQARDAILDGTHPVTQDKACEFAGIQVHIQFGPHNEAKHKTGFLDLKDFLPQSYVRTKG---IEKKIFSEHRKH 295
Cdd:cd14473     1 TRYLLYLQVKRDILEGRLPCSEETAALLAALALQAEYGDYDPSEHKPKYLSLKRFLPKQLLKQRKpeeWEKRIVELHKKL 80

                          90
                  ....*....|....*....
gi 442631073  296 VDLSEIDAKVLYTKTAREL 314
Cdd:cd14473    81 RGLSPAEAKLKYLKIARKL 99

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 442631073   88 RTLRVRMLDGAVKTILVDDSQPVSQLMVVICTKIGITNHEEyglvredneaqnenlpdnkfgtLTLKRKIMEKDRdakme 167
Cdd:cd17096     1 KTLRIQLPDLQYLDLRVDFSVKVFNAVVDLCKELGIRHPEE----------------------LSLLRPPLYRPK----- 53

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 442631073  168 SLRKKLKtddeMN--WVDVSRTLREQGIDEAETVLLRRRFF 206
Cdd:cd17096    54 SLVDKAR----LNsgWLDSSRSLMEQGVRENDTLLLRFKYY 90

Downstream of tyrosine kinase 4, 5, and 6 proteins phosphotyrosine-binding domain (PTBi); The Dok family adapters are phosphorylated by different protein tyrosine kinases. Dok proteins are involved in processes such as modulation of cell differentiation and proliferation, as well as in control of the cell spreading and migration The Dok protein contains an N-terminal pleckstrin homology (PH) domain followed by a central phosphotyrosine binding (PTB) domain, which has a PH-like fold, and a proline- and tyrosine-rich C-terminal tail. The PH domain binds to acidic phospholids and localizes proteins to the plasma membrane, while the PTB domain mediates protein-protein interactions by binding to phosphotyrosine-containing motifs. The C-terminal part of Dok contains multiple tyrosine phosphorylation sites that serve as potential docking sites for Src homology 2-containing proteins such as ras GTPase-activating protein and Nck, leading to inhibition of ras signaling pathway activation and the c-Jun N-terminal kinase (JNK) and c-Jun activation, respectively. There are 7 mammalian Dok members: Dok-1 to Dok-7. Dok-1 and Dok-2 act as negative regulators of the Ras-Erk pathway downstream of many immunoreceptor-mediated signaling systems, and it is believed that recruitment of p120 rasGAP by Dok-1 and Dok-2 is critical to their negative regulation. Dok-3 is a negative regulator of the activation of JNK and mobilization of Ca2+ in B-cell receptor-mediated signaling, interacting with SHIP-1 and Grb2. Dok-4- 6 play roles in protein tyrosine kinase(PTK)-mediated signaling in neural cells and Dok-7 is the key cytoplasmic activator of MuSK (Muscle-Specific Protein Tyrosine Kinase). PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the IRS-like subgroup.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 442631073  338 LLGVTKDSVLRLDEHT-KEILISWPLTTVRRWGASPNTFTLDFG---DYANQYYSVQTTEAEQIVQ 399
Cdd:cd13164    24 LLQITHENIYLWDIHNpRVKLVSWPLCSLRRYGRDSTWFTFEAGrmcDTGEGLFTFQTREGEQIYQ 89

FERM domain C-lobe of the Fermitin family; 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. 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). This cd is not included in the C-lobe hierarchy based on its position in the tree. One thing to note is that unlike the other members of the C-lobe hierarchy it contains 2 FERM M domains which might also reflect a difference in its evolutionary history. 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 442631073  317 YGVTFFLVKEKMNGKNKLvprlLGVTKDSVLRLDEHTKEILISWPLTTVRRWGASPNTFTL--DFGDyANQYYSVQTTEA 394
Cdd:cd13205     2 FGITYFIVRFRGSKKEEL----LGVAYNRLIRMDLHTGDPIKTWRYSTMKAWNVNWEIREViiQFED-ENIAFACLSADC 76

                          90
                  ....*....|.
gi 442631073  395 EQIVQLIAGYI 405
Cdd:cd13205    77 KIVHEFIGGYI 87