Allosteric activation of ADAMTS13 by von Willebrand factor
Allosteric activation of ADAMTS13 by von Willebrand factor
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DOI：
10.1073/pnas.1413282112
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发表时间：
2014-12-30
影响因子：
11.1
通讯作者：
Sadler, J. Evan
中科院分区：
文献类型：
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作者：
Muia, Joshua;Zhu, Jian;Sadler, J. Evan
金属蛋白酶ADAMTS13可裂解血管内血小板聚集物中的血管性血友病因子(VWF)，ADAMTS13缺乏可导致致命性微血管血栓形成。ADAMTS13的近端金属蛋白酶(M)、类去整合素(D)、凝血酶反应蛋白-1(T)、富含半胱氨酸(C)和间隔区(S)结构域识别VWF中一个被张力暴露的隐蔽部位。另外7个T和2个补体C1r/C1s、海胆表皮生长因子和骨形态发生蛋白(CUB)功能未知的结构域是MDTCS结构域的C末端。我们发现，远端的T8-CUB2结构域显著抑制底物切割，而VWF或单抗与远端的ADAMTS13结构域的结合解除了这种自身抑制。小角X射线散射数据表明，远端的T-cub结构域与近端的MDTCS结构域相互作用。因此，ADAMTS13受底物诱导的变构激活调节，这可能优化体内流体切应力下的VWF切割。其他ADAMTS酶的远端结构域可能具有类似的变构性质。
The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) within endovascular platelet aggregates, and ADAMTS13 deficiency causes fatal microvascular thrombosis. The proximal metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains of ADAMTS13 recognize a cryptic site in VWF that is exposed by tensile force. Another seven T and two complement C1r/C1s, sea urchin epidermal growth factor, and bone morphogenetic protein (CUB) domains of uncertain function are C-terminal to the MDTCS domains. We find that the distal T8-CUB2 domains markedly inhibit substrate cleavage, and binding of VWF or monoclonal antibodies to distal ADAMTS13 domains relieves this autoinhibition. Small angle X-ray scattering data indicate that distal T-CUB domains interact with proximal MDTCS domains. Thus, ADAMTS13 is regulated by substrate-induced allosteric activation, which may optimize VWF cleavage under fluid shear stress in vivo. Distal domains of other ADAMTS proteases may have similar allosteric properties.