Integrin inside-out signaling and the immunological synapse.
Integrin inside-out signaling and the immunological synapse.
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DOI：
10.1016/j.ceb.2011.10.004
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发表时间：
2012-02
影响因子：
7.5
通讯作者：
Dustin, Michael L.
中科院分区：
文献类型：
--
作者：
Springer, Timothy A.;Dustin, Michael L.
整合素在细胞表面的三种构象状态之间动态平衡。弯曲的构造具有封闭的头件。两种扩展构造包含封闭式或开放式头件。头件打开涉及混合结构域摆出和整合素膝盖处的 70 Å 分离，这是通过变构从 βI 结构域的混合近端传递到 βI 结构域另一端配体结合位点的 3 Å 重排。弯曲闭合和延伸闭合整合素的亲和力均较低，而延伸开放整合素亲和力则高103至104。整合素介导的粘附需要扩展的开放构象，其在生理背景下通过配体结合后事件来稳定。因此，整联蛋白区分底物结合配体和可溶性配体。对免疫突触中 LFA-1-ICAM-1 相互作用的分析表明，键寿命约为秒，这与受到细胞骨架力（增加解离率）的高亲和力相互作用一致。 LFA-1 βI 结构域拮抗剂消除了免疫突触的功能，进一步支持了高亲和力 LFA-1 的关键作用。
Integrins dynamically equilibrate between three conformational states on cell surfaces. A bent conformation has a closed headpiece. Two extended conformations contain either a closed or an open headpiece. Headpiece opening involves hybrid domain swing-out and a 70 Å separation at the integrin knees, which is conveyed by allostery from the hybrid-proximal end of the βI domain to a 3 Å rearrangement of the ligand-binding site at the opposite end of the βI domain. Both bent-closed and extended-closed integrins have low affinity, whereas extended-open integrin affinity is 103to 104higher. Integrin-mediated adhesion requires the extended-open conformation, which in physiological contexts is stabilized by post-ligand binding events. Integrins thus discriminate between substrate-bound and soluble ligands. Analysis of LFA-1-ICAM-1 interactions in the immunological synapse suggests that bond lifetimes are on the order of seconds, which is consistent with high affinity interactions subjected to cytoskeletal forces that increase the dissociation rate. LFA-1 βI domain antagonists abrogate function in the immunological synapse, further supporting a critical role for high affinity LFA-1.
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