美国波士顿儿童医院Timothy A. Springer等研究人员合作发现，配体结合启动单分子整合素构象激活。该研究于2024年5月20日在线发表于国际一流学术期刊《细胞》。

研究人员发现，单分子荧光动力学显示，配体与细胞表面占主导地位的弯曲封闭整合素构象结合后，会在几毫秒内发生两种协同变化，即腿部伸展和头部打开，从而产生高亲和性整合素构象。伸展-闭合整合素构象不是一个中间构象，但可以从伸展-开放构象直接进入，并为配体解离提供途径。

与配体相反，连接整合素β亚基胞质结构域与肌动蛋白细胞骨架的talin可适度稳定整合素，但不会诱导延伸或开放。因此，整合素的活化是由外入信号启动的，随后是内出信号。这些研究结果进一步表明，talin结合不足以激活由内而外的整合素，需要通过配体-整合素-talin-肌动蛋白细胞骨架复合物进行拉力传递。

据悉，在细胞迁移和粘附过程中，整合素将细胞外环境与肌动蛋白细胞骨架联系起来。细胞内外事件之间的快速协调至关重要。

附：英文原文

Title: Ligand binding initiates single-molecule integrin conformational activation

Author: Jing Li, Myung Hyun Jo, Jiabin Yan, Taylor Hall, Joon Lee, Uriel López-Sánchez, Sophia Yan, Taekjip Ha, Timothy A. Springer

Issue&Volume: 2024-05-20

Abstract: Integrins link the extracellular environment to the actin cytoskeleton in cell migration and adhesiveness. Rapid coordination between events outside and inside the cell is essential. Single-molecule fluorescence dynamics show that ligand binding to the bent-closed integrin conformation, which predominates on cell surfaces, is followed within milliseconds by two concerted changes, leg extension and headpiece opening, to give the high-affinity integrin conformation. The extended-closed integrin conformation is not an intermediate but can be directly accessed from the extended-open conformation and provides a pathway for ligand dissociation. In contrast to ligand, talin, which links the integrin β-subunit cytoplasmic domain to the actin cytoskeleton, modestly stabilizes but does not induce extension or opening. Integrin activation is thus initiated by outside-in signaling and followed by inside-out signaling. Our results further imply that talin binding is insufficient for inside-out integrin activation and that tensile force transmission through the ligand-integrin-talin-actin cytoskeleton complex is required.

DOI: 10.1016/j.cell.2024.04.049

Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00475-6