Mechanically Regulated Outside-In Activation of an I-Domain-Containing Integrin.
Mechanically Regulated Outside-In Activation of an I-Domain-Containing Integrin.
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DOI：
10.1016/j.bpj.2020.07.022
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发表时间：
2020-08
影响因子：
3.4
通讯作者：
Debin Mao;Shouqin Lü;Xiao Zhang;M. Long
中科院分区：
文献类型：
--
作者：
Debin Mao;Shouqin Lü;Xiao Zhang;M. Long
整合素是一种异二聚体跨膜蛋白，通过构象变构介导细胞黏附和双向机械转导。由于其复杂性和缺乏有效的实验，含有I结构域的整合素的变构途径仍然不清楚。对于一个典型的含有I结构域的整合素αXβ2，本文采用分子动力学模拟方法研究了外向内激活的前两个步骤--外部和内部配体的结合过程中的构象动力学。结果表明，α-亚基向β-亚基的变构传递和外力对整合素-配体复合体的作用是内源性配体结合的先决条件。αI结构域的开放状态和α7-螺旋的下移和下半部展开确保了亚基间稳定的构象传递，首先是外部配体结合，然后是内部配体结合。据我们所知，反向结合顺序诱导了β-亚基混合域的新颖但不稳定的摆动，保留了αI和βI结构域的关闭状态。外部配体的预结合极大地促进了以下内部配体结合，反之亦然。这些模拟从内部变构途径的角度进一步理解了含有I结构域的整合素由外而内的激活过程。
Integrins are heterodimeric transmembrane proteins that mediate cellular adhesion and bidirectional mechanotransductions through their conformational allostery. The allosteric pathway of an I-domain-containing integrin remains unclear because of its complexity and lack of effective experiments. For a typical I-domain-containing integrinαXβ2, molecular dynamics simulations were employed here to investigate the conformational dynamics in the first two steps of outside-in activation, the bindings of both the external and internal ligands. Results showed that the internal ligand binding is a prerequisite to the allosteric transmission from theα- toβ-subunits and the exertion of external force to integrin-ligand complex. The opening state ofαI domain with downward movement and lower half unfolding ofα7-helix ensures the stable intersubunit conformational transmission through external ligand binding first and internal ligand binding later. Reverse binding order induces a, to our knowledge, novel but unstable swingout ofβ-subunit Hybrid domain with the retained close states of bothαI andβI domains. Prebinding of external ligand greatly facilitates the following internal ligand binding and vice versa. These simulations furthered the understanding in the outside-in activation of I-domain-containing integrins from the viewpoint of internal allosteric pathways.