The Architecture of Talin1 Reveals an Autoinhibition Mechanism release_muyiozlxhrdexhv7aksjnmayda

by Dirk Dedden, Stephanie Schumacher, Charlotte F. Kelley, Martin Zacharias, Christian Biertümpfel, Reinhard Fässler, Naoko Mizuno

Published in Cell by Elsevier BV.

2019   Volume 179, Issue 1, p120-131.e13

Abstract

Focal adhesions (FAs) are protein machineries essential for cell adhesion, migration, and differentiation. Talin is an integrin-activating and tension-sensing FA component directly connecting integrins in the plasma membrane with the actomyosin cytoskeleton. To understand how talin function is regulated, we determined a cryoelectron microscopy (cryo-EM) structure of full-length talin1 revealing a two-way mode of autoinhibition. The actin-binding rod domains fold into a 15-nm globular arrangement that is interlocked by the integrin-binding FERM head. In turn, the rod domains R9 and R12 shield access of the FERM domain to integrin and the phospholipid PIP2 at the membrane. This mechanism likely ensures synchronous inhibition of integrin, membrane, and cytoskeleton binding. We also demonstrate that compacted talin1 reversibly unfolds to an ∼60-nm string-like conformation, revealing interaction sites for vinculin and actin. Our data explain how fast switching between active and inactive conformations of talin could regulate FA turnover, a process critical for cell adhesion and signaling.
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