Autoregulation of von Willebrand factor function by a disulfide bond switch.
Autoregulation of von Willebrand factor function by a disulfide bond switch.
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DOI：
10.1126/sciadv.aaq1477
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发表时间：
2018-03
期刊：
影响因子：
13.6
通讯作者：
Hogg PJ
中科院分区：
文献类型：
--
作者：
Butera D;Passam F;Ju L;Cook KM;Woon H;Aponte-Santamaría C;Gardiner E;Davis AK;Murphy DA;Bronowska A;Luken BM;Baldauf C;Jackson S;Andrews R;Gräter F;Hogg PJ
我们证明了血栓形成和止血中血小板与血管性血友病因子粘附的机械化学调节。血小板糖蛋白Ib（GPIb）受体与血浆血管性血友病因子（VWF）的力依赖性结合在止血和血栓形成中起关键作用。以前的研究表明，VWF激活需要力诱导的暴露的GPIb结合位点的A1域是自动抑制的邻近A2域。然而，这种“机械表达”的生物化学基础仍然难以捉摸。从蛋白质的化学，生物物理和功能的研究相结合，我们发现，自抑制是由一个不寻常的二硫键的氧化还原状态附近的羧基末端的A2结构域，连接相邻的半胱氨酸残基，形成一个八元环控制。只有当键被切割时，A2结构域才与A1结构域结合并阻断血小板GPIb结合。分子动力学模拟表明，裂解的二硫键修改的A2结构域的结构和分子应力在一个远程变构的方式，这提供了一个结构上的解释氧化还原控制的自抑制。值得注意的是，A2二硫键在健康人供体血浆中约75%的VWF亚基中裂解，但在接受体外膜氧合支持的心力衰竭患者中仅约25%的血浆VWF亚基中裂解。这表明大多数血小板GPIb的血浆VWF结合位点在健康供体中是自抑制的，但在心力衰竭患者中大多可用。这些发现表明二硫键开关调节VWF的机械呈递。
We demonstrate mechanochemical regulation of platelet adhesion to von Willebrand factor in thrombosis and hemostasis. Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this “mechanopresentation” remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring. Only when the bond is cleaved does the A2 domain bind to the A1 domain and block platelet GPIb binding. Molecular dynamics simulations indicate that cleavage of the disulfide bond modifies the structure and molecular stresses of the A2 domain in a long-range allosteric manner, which provides a structural explanation for redox control of the autoinhibition. Significantly, the A2 disulfide bond is cleaved in ~75% of VWF subunits in healthy human donor plasma but in just ~25% of plasma VWF subunits from heart failure patients who have received extracorporeal membrane oxygenation support. This suggests that the majority of plasma VWF binding sites for platelet GPIb are autoinhibited in healthy donors but are mostly available in heart failure patients. These findings demonstrate that a disulfide bond switch regulates mechanopresentation of VWF.
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Von Willebrand因子-A1结构域在具有独特的力依赖性解离动力学的多个状态下结合了血小板糖蛋白IBα。
影响因子：
7.5
作者：
Ju L;Chen Y;Zhou F;Lu H;Cruz MA;Zhu C
通讯作者：
Zhu C
影响因子：
1.2
作者：
Chen, Yunfeng;Liu, Baoyu;Zhu, Cheng
通讯作者：
Zhu, Cheng
影响因子：
2
作者：
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通讯作者：
Corthals, GL
影响因子：
20.3
作者：
Luken, Brenda M.;Winn, Luke Y. N.;Crawley, James T. B.
通讯作者：
Crawley, James T. B.
影响因子：
16.6
作者：
Bekendam, Roelof H.;Bendapudi, Pavan K.;Lin, Lin;Nag, Partha P.;Pu, Jun;Kennedy, Daniel R.;Feldenzer, Alexandra;Chiu, Joyce;Cook, Kristina M.;Furie, Bruce;Huang, Mingdong;Hogg, Philip J.;Flaumenhaft, Robert
通讯作者：
Flaumenhaft, Robert