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Journal Article

The Architecture of Talin1 Reveals an Autoinhibition Mechanism

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Dedden,  Dirk
Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;
Mizuno, Naoko / Cellular and Membrane Trafficking, Max Planck Institute of Biochemistry, Max Planck Society;

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Schumacher,  Stephanie
Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Kelley,  Charlotte
Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Biertümpfel,  Christian
Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;
Biertümpfel, Christian / Molecular Mechanisms of DNA Repair, Max Planck Institute of Biochemistry, Max Planck Society;

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Fässler,  Reinhard
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Mizuno,  Naoko
Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;
Mizuno, Naoko / Cellular and Membrane Trafficking, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Dedden, D., Schumacher, S., Kelley, C., Zacharias, M., Biertümpfel, C., Fässler, R., et al. (2019). The Architecture of Talin1 Reveals an Autoinhibition Mechanism. CELL, 179(1), 120-131.e13. doi:10.1016/j.cell.2019.08.034.


Cite as: https://hdl.handle.net/21.11116/0000-0005-6B8A-8
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 d 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 similar to 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.