近日，德国马克斯·普朗克生物化学研究所Naoko Mizuno及其小组利用Talin1蛋白的结构揭示了一种自抑制机制。相关论文于2019年9月19日发表于国际学术期刊《细胞》上。

为了理解talin功能是如何被调节的，研究人员确定了全长talin1的冷冻电镜结构，揭示了双向自抑制模式。肌动蛋白结合杆结构域折叠成15nm的球状排列，其由整联蛋白结合的FERM头部互锁。反过来，杆区域R9和R12屏蔽FERM结构域进入整联蛋白和膜上的磷脂PIP2。该机制可能确保整联蛋白、膜和细胞骨架结合的同步抑制。研究人员还证明了压缩的talin1能够可逆地展开到~60-nm的弦状构象，从而揭示了vinculin蛋白和肌动蛋白的相互作用位点。这些数据解释了talin的活性和非活性构象之间的快速转换可以调节粘着斑（FA）转换，这是细胞粘附和信号传导的关键过程。

研究人员表示，FA是细胞粘附、迁移和分化所必需的蛋白质机器。talin是整联蛋白激活和张力感应FA成分，其直接连接质膜中的整联蛋白与肌动球蛋白细胞骨架。

附：英文原文

Title: The Architecture of Talin1 Reveals an Autoinhibition Mechanism

Author: Dirk Dedden, Stephanie Schumacher, Charlotte F. Kelley, Martin Zacharias, Christian Biertümpfel, Reinhard Fssler, Naoko Mizuno

Issue&Volume: Volume 179 Issue 1

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.

DOI: 10.1016/j.cell.2019.08.034

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30953-5