Integrin conformational regulation: Uncoupling extension/tail separation from changes in the head region by a multiresolution approach
Integrin conformational regulation: Uncoupling extension/tail separation from changes in the head region by a multiresolution approach
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DOI：
10.1016/j.str.2008.02.019
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发表时间：
2008-06-01
期刊：
影响因子：
5.7
通讯作者：
Hantgan, Roy R.
中科院分区：
文献类型：
--
作者：
Rocco, Mattia;Rosano, Camillo;Hantgan, Roy R.
整合素依赖的粘附和信号传导受构象变化的调节，其细节仍有争议。晶体学显示弯曲的形状休息和引发整合素胞外域，而大的，配体诱导的重排在其他结构中建议的延伸，“开放”和尾部分离。我们已经使用实验/计算流体力学来区分不同的α（v）β（3）和α（IIb）β（3）原子模型建立在X射线，NMR和EM数据。与X射线结构和EM图相反，流体动力学表明静息整合素已经扩展。此外，α（v）β（3）胞外域-纤连蛋白片段复合物的流体动力学支持通过额外的头部区域构象变化（杂交结构域摆动）打开，但没有尾部分离。同样，在一个扩展的、基于电子断层扫描的模型中，全长α（IIb）β（3）中由引发剂诱导的摩擦变化与与简单跨膜螺旋移位耦合的摆动密切相关。延伸和立即尾部分离，然后从激活后的头部区域重排解偶联，从而强调整合素的微妙，微调可塑性。
Integrin-dependent adhesion and signaling are regulated by conformational changes whose details remain controversial. Crystallography revealed bent shapes for resting and primed integrin ectodomains, whereas large, ligand-induced rearrangements in other constructs suggested extension, "opening," and tail separation. We have used experimental/ computed hydrodynamics to discriminate among different alpha(v)beta(3) and alpha(IIb)beta(3) atomic models built on X-ray, NMR, and EM data. In contrast with X-ray structures and EM maps, hydrodynamics indicate that resting integrins are already extended. Furthermore, the hydrodynamics of an alpha(v)beta(3) ectodomain-fibronectin fragment complex support opening via additional head region conformational changes (hybrid domain swing-out), but without tail separation. Likewise, frictional changes induced by priming agents in full-length alpha(IIb)beta(3) correlate well with the swing-out coupled to a simple transmembrane helix shift in an extended, electron tomography-based model. Extension and immediate tail separation are then uncoupled from head region rearrangements following activation, thus underscoring integrins' delicate, finely tuned plasticity.