Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
Faculty of Medicine and Health Technology, Tampere University, FI-33520 Tampere, Finland.
Proc Natl Acad Sci U S A. 2020 Dec 22;117(51):32402-32412. doi: 10.1073/pnas.2014583117. Epub 2020 Dec 7.
Binding of the intracellular adapter proteins talin and its cofactor, kindlin, to the integrin receptors induces integrin activation and clustering. These processes are essential for cell adhesion, migration, and organ development. Although the talin head, the integrin-binding segment in talin, possesses a typical FERM-domain sequence, a truncated form has been crystallized in an unexpected, elongated form. This form, however, lacks a C-terminal fragment and possesses reduced β3-integrin binding. Here, we present a crystal structure of a full-length talin head in complex with the β3-integrin tail. The structure reveals a compact FERM-like conformation and a tightly associated N-P-L-Y motif of β3-integrin. A critical C-terminal poly-lysine motif mediates FERM interdomain contacts and assures the tight association with the β3-integrin cytoplasmic segment. Removal of the poly-lysine motif or disrupting the FERM-folded configuration of the talin head significantly impairs integrin activation and clustering. Therefore, structural characterization of the FERM-folded active talin head provides fundamental understanding of the regulatory mechanism of integrin function.
细胞内衔接蛋白 talin 和其辅助因子 kindlin 与整合素受体的结合会诱导整合素的激活和聚集。这些过程对于细胞黏附、迁移和器官发育是必不可少的。尽管 talin 头部（talin 中的整合素结合片段）具有典型的 FERM 结构域序列，但已结晶出一种截断形式，其呈现出意想不到的伸长形式。然而，这种形式缺少一个 C 端片段，并且与β3 整合素的结合减少。在这里，我们展示了一个全长 talin 头部与β3 整合素尾部复合物的晶体结构。该结构揭示了一个紧凑的 FERM 样构象和一个紧密相关的β3 整合素 N-P-L-Y 基序。一个关键的 C 端多赖氨酸基序介导了 FERM 结构域间的接触，并确保与β3 整合素胞质段的紧密结合。去除多赖氨酸基序或破坏 talin 头部的 FERM 折叠构象会显著损害整合素的激活和聚集。因此，对 FERM 折叠活性 talin 头部的结构特征进行分析，为整合素功能的调控机制提供了基本的认识。
