Acebrón, Iván and Righetto, Ricardo D. and Schoenherr, Christina and de Buhr, Svenja and Redondo, Pilar and Culley, Jayne and Rodríguez, Carlos F. and Daday, Csaba and Biyani, Nikhil and Llorca, Oscar and Byron, Adam and Chami, Mohamed and Gräter, Frauke and Boskovic, Jasminka and Frame, Margaret C. and Stahlberg, Henning and Lietha, Daniel. (2020) Structural basis of Focal Adhesion Kinase activation on lipid membranes. The EMBO Journal, 39 (19 ). e104743.
|
PDF
- Published Version
4Mb |
Official URL: https://edoc.unibas.ch/78617/
Downloads: Statistics Overview
Abstract
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.
Faculties and Departments: | 05 Faculty of Science > Departement Biozentrum > Services Biozentrum > BioEM Lab (Chami) |
---|---|
UniBasel Contributors: | Chami, Mohamed |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
Publisher: | Nature Publishing Group |
ISSN: | 0261-4189 |
e-ISSN: | 1460-2075 |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Language: | English |
Identification Number: |
|
edoc DOI: | |
Last Modified: | 27 Jan 2022 13:44 |
Deposited On: | 19 Jan 2022 15:59 |
Repository Staff Only: item control page