Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/218091
Share/Export:
logo share SHARE logo core CORE BASE
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE
Title

Structural basis of Focal Adhesion Kinase activation on lipid membranes

AuthorsAcebrón, Iván CSIC ORCID; Righetto, Ricardo D.; Schoenherr, Christina; de Buhr, Svenja; Redondo, Pilar; Culley, Jayne; Rodríguez, Carlos F.; Daday, Csaba; Biyani, Nikhil; Llorca, Óscar; Byron, Adam; Chami, Mohamed; Gräter, Frauke; Boskovic, Jasminka; Frame, Margaret C.; Stahlberg, Henning; Lietha, Daniel CSIC ORCID
KeywordsCell adhesion
Cryo-electron microscopy (cryo-EM)
Focal adhesion kinase
Membrane complex
Phosphatidylinositol-4,5-bisphosphate
Issue Date11-Aug-2020
PublisherEMBO Press
CitationThe EMBO Journal e104743 (2020)
AbstractFocal 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.
Description21 p.-9 fig.-2 tab.
Publisher version (URL)https://doi.org/10.15252/embj.2020104743
URIhttp://hdl.handle.net/10261/218091
DOI10.15252/10.15252/embj.2020104743.2020104743
ISSN0261-4189
E-ISSN1460-2075
Appears in Collections:(CIB) Artículos

Files in This Item:
File Description SizeFormat
embj_Acebrón_2020.pdfArtículo principal5,81 MBAdobe PDFThumbnail
View/Open
Show full item record
Review this work

Page view(s)

137
checked on Jan 24, 2022

Download(s)

215
checked on Jan 24, 2022

Google ScholarTM

Check

Altmetric

Dimensions


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.