2026-08-13T00:20:45Zhttps://repisalud.isciii.es/rest/oai/request
oai:repisalud.isciii.es:20.500.12105/230872024-11-30T00:10:34Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud author Acebrón, Iván author Righetto, Ricardo D author Schoenherr, Christina author de Buhr, Svenja author Redondo, Pilar author Culley, Jayne author Rodríguez, Carlos F author Daday, Csaba author Biyani, Nikhil author Llorca Blanco, Oscar Antonio author Byron, Adam author Chami, Mohamed author Gräter, Frauke author Boskovic, Jasminka author Frame, Margaret C author Stahlberg, Henning author Lietha, Daniel funder Jose Castillejo Mobility Grant by the Spanish Ministry of Education, Culture and Sports funder Werner-Siemens Foundation funder Swiss National Science Foundation (SNSF) funder University of Basel funder Klaus Tschira Foundation funder German Research Foundation (DFG) funder Carl Zeiss Foundation funder Cancer Research UK (Reino Unido) funder Consejo Superior de Investigaciones Científicas (España) funder Ministerio de Ciencia, Innovación y Universidades (España) funder Instituto de Salud Carlos III 2024-09-16T08:16:58Z 2024-09-16T08:16:58Z 2020-10-01 EMBO J . 2020 ;39(19):e104743. 10.15252/embj.2020104743 1460-2075 The EMBO journal 32779739 https://hdl.handle.net/20.500.12105/23087 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. eng Structural basis of Focal Adhesion Kinase activation on lipid membranes. research article