Structural basis of integrin activation by talin

被引:550
作者
Wegener, Kate L.
Partridge, Anthony W.
Han, Jaewon
Pickford, Andrew R.
Liddington, Robert C.
Ginsberg, Mark H. [1 ]
Campbell, Iain D.
机构
[1] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England
[2] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[3] Burnham Inst, Ctr Canc, Program Cell Adhes, La Jolla, CA 92037 USA
[4] Univ Portsmouth, Portsmouth PO1 2DY, Hants, England
基金
英国惠康基金;
关键词
D O I
10.1016/j.cell.2006.10.048
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Regulation of integrin affinity (activation) is essential for metazoan development and for many pathological processes. Binding of the talin phosphotyrosine-binding (PTB) domain to integrin beta subunit cytoplasmic domains (tails) causes activation, whereas numerous other PTB-domain-containing proteins bind integrins without activating them. Here we define the structure of a complex between talin and the membrane-proximal integrin beta 3 cytoplasmic domain and identify specific contacts between talin and the integrin tail required for activation. We used structure-based mutagenesis to engineer talin and beta 3 variants that interact with comparable affinity to the wild-type proteins but inhibit integrin activation by competing with endogenous talin. These results reveal the structural basis of talin's unique ability to activate integrins, identify an interaction that could aid in the design of therapeutics to block integrin activation, and enable engineering of cells with defects in the activation of multiple classes of integrins.
引用
收藏
页码:171 / 182
页数:12
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