Structural basis of Focal Adhesion Kinase activation on lipid membranes.

Autor: Acebrón I; Structural Biology Programme, Spanish National Cancer Research Centre, Madrid, Spain., Righetto RD; Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland., Schoenherr C; Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., de Buhr S; Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany., Redondo P; Structural Biology Programme, Spanish National Cancer Research Centre, Madrid, Spain., Culley J; Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Rodríguez CF; Structural Biology Programme, Spanish National Cancer Research Centre, Madrid, Spain., Daday C; Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany., Biyani N; Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland., Llorca O; Structural Biology Programme, Spanish National Cancer Research Centre, Madrid, Spain., Byron A; Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Chami M; Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland., Gräter F; Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany., Boskovic J; Structural Biology Programme, Spanish National Cancer Research Centre, Madrid, Spain., Frame MC; Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Stahlberg H; Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland., Lietha D; Structural Biology Programme, Spanish National Cancer Research Centre, Madrid, Spain.; Centro de Investigaciones Biológicas Margarita Salas, Spanish National Research Council (CSIC), Madrid, Spain.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2020 Oct 01; Vol. 39 (19), pp. e104743. Date of Electronic Publication: 2020 Aug 11.
DOI: 10.15252/embj.2020104743
Abstrakt: Focal adhesion kinase (FAK) is a key component of the membrane proximal signaling layer in focal adhesion complexes, regulating important cellular processes, including cell migration, proliferation, and survival. In the cytosol, FAK adopts an autoinhibited state but is activated upon recruitment into focal adhesions, yet how this occurs or what induces structural changes is unknown. Here, we employ cryo-electron microscopy to reveal how FAK associates with lipid membranes and how membrane interactions unlock FAK autoinhibition to promote activation. Intriguingly, initial binding of FAK to the membrane causes steric clashes that release the kinase domain from autoinhibition, allowing it to undergo a large conformational change and interact itself with the membrane in an orientation that places the active site toward the membrane. In this conformation, the autophosphorylation site is exposed and multiple interfaces align to promote FAK oligomerization on the membrane. We show that interfaces responsible for initial dimerization and membrane attachment are essential for FAK autophosphorylation and resulting cellular activity including cancer cell invasion, while stable FAK oligomerization appears to be needed for optimal cancer cell proliferation in an anchorage-independent manner. Together, our data provide structural details of a key membrane bound state of FAK that is primed for efficient autophosphorylation and activation, hence revealing the critical event in integrin mediated FAK activation and signaling at focal adhesions.
(© 2020 The Authors.)
Databáze: MEDLINE
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