Program in Cellular and Molecular Medicine, 2 Department of Medicine, 3 Department of Anethesiology, 4 Children's Hospital Boston, and 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
J Cell Biol. 2013 Nov 25;203(4):629-42. doi: 10.1083/jcb.201308083.
How is massive conformational change in integrins achieved on a rapid timescale? We report crystal structures of a metastable, putative transition state of integrin αXβ2. The αXβ2 ectodomain is bent; however, a lattice contact stabilizes its ligand-binding αI domain in a high affinity, open conformation. Much of the αI α7 helix unwinds, loses contact with the αI domain, and reshapes to form an internal ligand that binds to the interface between the β propeller and βI domains. Lift-off of the αI domain above this platform enables a range of extensional and rotational motions without precedent in allosteric machines. Movements of secondary structure elements in the β2 βI domain occur in an order different than in β3 integrins, showing that integrin β subunits can be specialized to assume different intermediate states between closed and open. Mutations demonstrate that the structure trapped here is metastable and can enable rapid equilibration between bent and extended-open integrin conformations and up-regulation of leukocyte adhesiveness.
整合素如何在快速的时间尺度上实现大规模构象变化？我们报告了整合素αXβ2 一种亚稳态、假定的过渡态的晶体结构。αXβ2 胞外结构域弯曲；然而，晶格接触稳定了其配体结合的αI 结构域处于高亲和力的开放构象。αIα7 螺旋的大部分解开，与αI 结构域失去接触，并重塑形成一个内部配体，与β 推进器和βI 结构域之间的界面结合。αI 结构域在这个平台上方的抬起使得一系列前所未有的伸展和旋转运动成为可能。β2βI 结构域中的二级结构元件的运动发生的顺序与β3 整合素不同，表明整合素β 亚基可以专门在关闭和打开之间的不同中间状态下发挥作用。突变表明，这里捕获的结构是亚稳态的，可以使弯曲和伸展开放的整合素构象之间快速达到平衡，并上调白细胞黏附性。
