The F1 loop of the talin head domain acts as a gatekeeper in integrin activation and clustering

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Kukkurainen , S , Azizi , L , Zhang , P , Jacquier , M-C , Baikoghli , M , von Essen , M , Tuukkanen , A , Laitaoja , M , Liu , X , Rahikainen , R , Orlowski , A , Jänis , J , Määttä , J A E , Varjosalo , M , Vattulainen , I , Rog , T , Svergun , D , Cheng , R H , Wu , J , Hytönen , V P & Wehrle-Haller , B 2020 , ' The F1 loop of the talin head domain acts as a gatekeeper in integrin activation and clustering ' , Journal of Cell Science , vol. 133 , no. 19 , 239202 . https://doi.org/10.1242/jcs.239202

Title: The F1 loop of the talin head domain acts as a gatekeeper in integrin activation and clustering
Author: Kukkurainen, Sampo; Azizi, Latifeh; Zhang, Pingfeng; Jacquier, Marie-Claude; Baikoghli, Mo; von Essen, Magdalena; Tuukkanen, Anne; Laitaoja, Mikko; Liu, Xiaonan; Rahikainen, Rolle; Orlowski, Adam; Jänis, Janne; Määttä, Juha A. E.; Varjosalo, Markku; Vattulainen, Ilpo; Rog, Tomasz; Svergun, Dmitri; Cheng, R. Holland; Wu, Jinhua; Hytönen, Vesa P.; Wehrle-Haller, Bernhard
Other contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Biosciences
University of Helsinki, Department of Physics
University of Helsinki, Department of Physics



Date: 2020-10
Language: eng
Number of pages: 15
Belongs to series: Journal of Cell Science
ISSN: 0021-9533
DOI: https://doi.org/10.1242/jcs.239202
URI: http://hdl.handle.net/10138/335158
Abstract: Integrin activation and clustering by talin are early steps of cell adhesion. Membrane-bound talin head domain and kindlin bind to the beta integrin cytoplasmic tail, cooperating to activate the heterodimeric integrin, and the talin head domain induces integrin clustering in the presence of Mn2+. Here we show that kindlin-1 can replace Mn2+ to mediate beta 3 integrin clustering induced by the talin head, but not that induced by the F2-F3 fragment of talin. Integrin clustering mediated by kindlin-1 and the talin head was lost upon deletion of the flexible loop within the talin head F1 subdomain. Further mutagenesis identified hydrophobic and acidic motifs in the F1 loop responsible for beta 3 integrin clustering. Modeling, computational and cysteine crosslinking studies showed direct and catalytic interactions of the acidic F1 loop motif with the juxtamembrane domains of alpha- and beta 3-integrins, in order to activate the beta 3 integrin heterodimer, further detailing the mechanism by which the talin-kindlin complex activates and clusters integrins. Moreover, the F1 loop interaction with the beta 3 integrin tail required the newly identified compact FERM fold of the talin head, which positions the F1 loop next to the inner membrane clasp of the talin-bound integrin heterodimer. This article has an associated First Person interview with the first author of the paper.
Subject: Activation
Cell adhesion
Clustering
Integrin
Molecular dynamics
Talin
BINDING-LIKE DOMAIN
X-RAY-SCATTERING
STRUCTURAL BASIS
MONOCLONAL-ANTIBODY
CELL-ADHESION
FERM DOMAIN
KINDLIN-3
SEQUENCE
SITES
AUTOINHIBITION
1182 Biochemistry, cell and molecular biology
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