Prediction of spacer-α6 complex: a novel insight into binding of ADAMTS13 with A2 domain of von Willebrand factor under forces.
Prediction of spacer-α6 complex: a novel insight into binding of ADAMTS13 with A2 domain of von Willebrand factor under forces.
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间隔-α 6 复合物的预测：对 ADAMTS13 与 von Willebrand 因子 A2 结构域在力作用下结合的新见解
DOI：
10.1038/s41598-018-24212-6
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发表时间：
2018-04-10
影响因子：
4.6
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Fang X;Lin J;Fang Y;Wu J
ADAMTS13对血管性血友病因子(VWF)A2结构域的强制调控切割是预防血栓性血小板减少性紫癜(TTP)的关键事件。识别和切割依赖于几个ADAMTS13亚域和vWF A2结构域的离散片段之间的合作和模块接触。ADAMTS13的间隔区含有一个重要的外切酶，与其A2区的α6螺旋相互作用，但目前尚不清楚α6的拉伸是否调节与间隔区的结合。为了了解在拉伸状态下间隔子与α6相互作用的分子机制，我们利用一种新的计算机策略结合导向分子动力学和柔性对接技术成功地预测了间隔子-α6复合体。该策略包括三个步骤：(1)α6的恒速贴片模拟；(2)α6的零速贴片模拟；(3)α6与间隔物的柔性对接。在我们的间隔区-α6复合体模型中，鉴定了13个关键残基，其中6个在α6中，7个在间隔区。我们的数据显示了α6与间隔区的两相延伸调节结合。络合物的结合强度随着α6的延伸而增加，直到达到最适的0.2 5 nm，然后随着α6延伸的进一步增加而降低，这意味着间隔区有利于与部分延伸的α6结合，这可能有助于最佳的接触和蛋白降解。界面面积和分子间盐桥的变化可能是这一特性的分子基础。这些发现为研究力作用下ADAMTS13和vWF A2结构域相互作用的机械力化学调控提供了新的见解。
Force-regulated cleavage of A2 domain of von Willebrand factor (vWF) by ADAMTS13 is a key event in preventing thrombotic thrombocytopenic purpura (TTP). Recognition and cleavage depend on cooperative and modular contacts between several ADAMTS13 subdomains and discrete segments of vWF A2 domain. Spacer domain of ADAMTS13 contains an important exosite interacting with α6 helix of unfold A2 domain, but it remains unclear whether stretching of α6 regulates binding to spacer. To understand the molecular mechanism underlying the interactions between spacer and α6 under stretching, we successfully predicted spacer-α6 complex by a novel computer strategy combined the steered molecular dynamics (SMD) and flexible docking techniques. This strategy included three steps: (1) constant-velocity SMD simulation of α6; (2) zero-velocity SMD simulations of α6, and (3) flexible dockings of α6 to spacer. In our spacer-α6 complex model, 13 key residues, six in α6 and seven in spacer, were identified. Our data demonstrated a biphasic extension-regulated binding of α6 to spacer. The binding strength of the complex increased with α6 extension until it reaches its optimum of 0.25 nm, and then decreased as α6 extension further increased, meaning that spacer is in favor to binding with a partially extended α6, which may contribute to the optimal contact and proteolysis. Changes of interface area and intermolecular salt bridge may serve as the molecular basis for this characteristic. These findings provide a novel insight into mechano-chemical regulation on interaction between ADAMTS13 and vWF A2 domain under forces.
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影响因子：
3.4
作者：
Di Stasio, Enrico;Lancellotti, Stefano;De Cristofaro, Raimondo
通讯作者：
De Cristofaro, Raimondo
影响因子：
14.9
作者：
Tina KG;Bhadra R;Srinivasan N
通讯作者：
Srinivasan N
影响因子：
5.6
作者：
Meszaros, Balint;Tompa, Peter;Dosztanyi, Zsuzsanna
通讯作者：
Dosztanyi, Zsuzsanna
影响因子：
20.3
作者：
Arya, M;Anvari, B;López, JA
通讯作者：
López, JA
影响因子：
20.3
作者：
Jin, Sheng-Yu;Skipwith, Christopher G.;Zheng, X. Long
通讯作者：
Zheng, X. Long