The Architecture of Talin1 Reveals an Autoinhibition Mechanism

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. [Display omitted] •The structure of the autoinhibited human full-length talin1 was analyzed by cryo-EM•Talin1 reversibly changes between a 15-nm closed and a ∼60-nm open conformation•Rod R9/R12 and FERM domains synchronously shield membrane and cytoskeleton binding•F-Actin and vinculin binding to talin is regulated by the opening of talin Structural characterization of talin shows how autoinhibition regulates interactions crucial for cell-cell contact and tension sensing.