Activation of leukocyte β2 integrins by conversion from bent to extended conformations
Activation of leukocyte β2 integrins by conversion from bent to extended conformations
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DOI：
10.1016/j.immuni.2006.07.016
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发表时间：
2006-10-01
期刊：
影响因子：
32.4
通讯作者：
Springer, Timothy A.
中科院分区：
文献类型：
--
作者：
Nishida, Noritaka;Xie, Can;Springer, Timothy A.
我们使用负染色电子显微镜（EM）检查激活白细胞整合素α（X）β（2）和α（L）β（2）所需的胞外域构象变化。它们在弯曲形态和两种延伸形态之间过渡，其中头盔处于闭合或打开状态。扩展的整合素表现出显着的灵活性，在α亚基α和整合素表皮生长因子样（I-EGF）结构域1和2之间。模拟整合素α和β亚基之间的跨膜结合的卡环强烈稳定了α（X）β（2）的弯曲构象，而α（L）β（2）的弯曲构象较弱。小分子变构拮抗剂诱导延伸的开放头片段构象。已知激活白细胞上的β（2）整合素的Fab诱导延伸，并且激活的Fab报告子仅在延伸被诱导后结合。结果建立了β 2整合素的延伸与其在免疫应答和白细胞运输中的活化之间的密切关系。
We used negative stain electron microscopy (EM) to examine the conformational changes in the ectodomains required for activation of the leukocyte integrins alpha(X)beta(2) and alpha(L)beta(2). They transitioned between a bent conformation and two extended conformations in which the headpiece was in either a closed or an open state. Extended integrins exhibited marked flexibility at the alpha subunit genu and between integrin epidermal growth factor-like (I-EGF) domains 1 and 2. A clasp to mimic juxtamembrane association between the integrin alpha and beta subunits stabilized the bent conformation strongly for alpha(X)beta(2) and less so for alpha(L)beta(2). A small molecule allosteric antagonist induced the extended, open headpiece conformation. A Fab known to activate beta(2) integrins on leukocytes induced extension, and a Fab reporter of activation bound only after extension had been induced. The results establish an intimate relationship between extension of beta(2) integrins and their activation in immune responses and leukocyte trafficking.