Molecular Playground/FAK: Difference between revisions
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<applet load='1MP8' size='400' color='black' frame='true' align='right' caption='Crystal structure of Focal Adhesion Kinase (FAK) kinase domain complex with ADP [[1mp8]]'/> | |||
<applet load='1MP8' size=' | |||
===Background=== | ===Background=== | ||
Focal adhesion kinase (FAK) is a protein tyrosine kinase which is recruited at an early stage to focal adhesions and which mediates many of the downstream responses. FAK plays a very important role in integrin-mediated signaling and in modulating such processes as cell growth, differentiation, wound healing, and tumor metastasis. | '''Focal adhesion kinase (FAK)''' is a protein tyrosine kinase which is recruited at an early stage to focal adhesions and which mediates many of the downstream responses. FAK plays a very important role in integrin-mediated signaling and in modulating such processes as cell growth, differentiation, wound healing, and tumor metastasis. | ||
===Structure=== | ===Structure=== | ||
Focal adhesion kinase (FAK) activation by phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-induced conformational change. In the inactive state, FAK adopts a closed, auto-inhibited conformation through interactions between its four-point-one, ezrin, radixin, moesin (FERM) and kinase domains. | Focal adhesion kinase (FAK) activation by phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-induced conformational change. In the inactive state, FAK adopts a closed, auto-inhibited conformation through interactions between its four-point-one, ezrin, radixin, moesin (FERM) and kinase domains. | ||
<scene name='User:Dannielle_Ryman/Sandbox_1/Fak_solution/3'>NMR solution structure of the focal adhesion targeting domain of focal adhesion kinase in complex with a paxillin LD peptide: evidence for a two-site binding model.</scene>Focal adhesion kinase (FAK) contains a FERM (protein 4.1, ezrin, radixin and moesin homology) domain, a kinase domain and a focal adhesion targeting (FAT) domain. The FAT domain recruits FAK to focal contacts by associating with integrin-associated proteins such as talin and paxillin. It also links FAK to the activation of Rho GTPases by binding to guanine nucleotide-exchange factors (GEFs) such as p190 RhoGEF. FAK contains three proline-rich regions (PRR1–3), which bind Src-homology-3 (SH3) domain-containing proteins such as p130Cas, the GTPase regulator associated with FAK (GRAF) and the Arf-GTPase-activating protein ASAP1. FAK is phosphorylated (P) on several tyrosine residues, including Tyr397, 407, 576, 577, 861 and 925. Tyrosine phosphorylation on Tyr397 creates a Src-homology-2 (SH2) binding site for Src, phospholipase Cgamma (PLCgamma), suppressor of cytokine signalling (SOCS), growth-factor-receptor-bound protein 7 (GRB7), the Shc adaptor protein, p120 RasGAP and the p85 subunit of phosphatidylinositol 3-kinase (PI3K). Phosphorylation of Tyr576 and Tyr577 within the kinase domain is required for maximal FAK catalytic activity, whereas the binding of FAK-family interacting protein of 200 kDa (FIP200) to the kinase region inhibits FAK catalytic activity. FAK phosphorylation at Tyr925 creates a binding site for GRB2.<scene name='User:Dannielle_Ryman/Sandbox_1/Fak2/2'>Crystal Structure of Focal Adhesion Kinase Domain with 2 molecules in the Asymmetric Unit Complexed with ADP and ATP</scene> | |||
==3D structures of focal adhesion kinase== | |||
Focal adhesion kinase | [[Focal adhesion kinase]] | ||
==References== | |||
1. Noble, Molecular Biophysics, 2001 | 1. Noble, Molecular Biophysics, 2001 | ||
Latest revision as of 14:54, 14 February 2016
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BackgroundBackground
Focal adhesion kinase (FAK) is a protein tyrosine kinase which is recruited at an early stage to focal adhesions and which mediates many of the downstream responses. FAK plays a very important role in integrin-mediated signaling and in modulating such processes as cell growth, differentiation, wound healing, and tumor metastasis.
StructureStructure
Focal adhesion kinase (FAK) activation by phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-induced conformational change. In the inactive state, FAK adopts a closed, auto-inhibited conformation through interactions between its four-point-one, ezrin, radixin, moesin (FERM) and kinase domains. Focal adhesion kinase (FAK) contains a FERM (protein 4.1, ezrin, radixin and moesin homology) domain, a kinase domain and a focal adhesion targeting (FAT) domain. The FAT domain recruits FAK to focal contacts by associating with integrin-associated proteins such as talin and paxillin. It also links FAK to the activation of Rho GTPases by binding to guanine nucleotide-exchange factors (GEFs) such as p190 RhoGEF. FAK contains three proline-rich regions (PRR1–3), which bind Src-homology-3 (SH3) domain-containing proteins such as p130Cas, the GTPase regulator associated with FAK (GRAF) and the Arf-GTPase-activating protein ASAP1. FAK is phosphorylated (P) on several tyrosine residues, including Tyr397, 407, 576, 577, 861 and 925. Tyrosine phosphorylation on Tyr397 creates a Src-homology-2 (SH2) binding site for Src, phospholipase Cgamma (PLCgamma), suppressor of cytokine signalling (SOCS), growth-factor-receptor-bound protein 7 (GRB7), the Shc adaptor protein, p120 RasGAP and the p85 subunit of phosphatidylinositol 3-kinase (PI3K). Phosphorylation of Tyr576 and Tyr577 within the kinase domain is required for maximal FAK catalytic activity, whereas the binding of FAK-family interacting protein of 200 kDa (FIP200) to the kinase region inhibits FAK catalytic activity. FAK phosphorylation at Tyr925 creates a binding site for GRB2.
3D structures of focal adhesion kinase3D structures of focal adhesion kinase
ReferencesReferences
1. Noble, Molecular Biophysics, 2001
2. Satyajit K. Mitra. Nature Reviews, 2005
3. Margaret C. Frame. Nature Reviews, 2010