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Kukkurainen S , Azizi L , Zhang P , Jacquier MC , Baikoghli M , von Essen M , Tuukkanen A , Laitaoja M , Liu X , Rahikainen R , Orłowski A , Jänis J , Määttä JAE , Varjosalo M , Vattulainen I , Róg T , Svergun D , Cheng RH , Wu J , Hytönen VP , Wehrle-Haller B
The F1 loop of the talin head domain acts as a gatekeeper in integrin activation and clustering
J Cell Sci. 2020 Oct 12;133(19)
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Integrin activation and clustering by talin are early steps of cell adhesion. Membrane-bound talin head domain and kindlin bind to the β integrin cytoplasmic tail, cooperating to activate the heterodimeric integrin, and the talin head domain induces integrin clustering in the presence of Mn(2+) Here we show that kindlin-1 can replace Mn(2+) to mediate β3 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 β3 integrin clustering. Modeling, computational and cysteine crosslinking studies showed direct and catalytic interactions of the acidic F1 loop motif with the juxtamembrane domains of α- and β3-integrins, in order to activate the β3 integrin heterodimer, further detailing the mechanism by which the talin-kindlin complex activates and clusters integrins. Moreover, the F1 loop interaction with the β3 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.
1477-9137 Kukkurainen, Sampo Orcid: 0000-0002-0635-784x Azizi, Latifeh Zhang, Pingfeng Orcid: 0000-0001-5985-4914 Jacquier, Marie-Claude Baikoghli, Mo von Essen, Magdaléna Orcid: 0000-0002-2412-6316 Tuukkanen, Anne Laitaoja, Mikko Liu, Xiaonan Rahikainen, Rolle Orłowski, Adam Jänis, Janne Määttä, Juha A E Varjosalo, Markku Orcid: 0000-0002-1340-9732 Vattulainen, Ilpo Orcid: 0000-0001-7408-3214 Róg, Tomasz Svergun, Dmitri Cheng, R Holland Wu, Jinhua Orcid: 0000-0001-5913-0633 Hytönen, Vesa P Orcid: 0000-0002-9357-1480 Wehrle-Haller, Bernhard Orcid: 0000-0002-1159-1147 Journal Article England J Cell Sci. 2020 Oct 12;133(19):jcs239202. doi: 10.1242/jcs.239202.