A new redox switch regulating von Willebrand factor activity.
A new redox switch regulating von Willebrand factor activity.
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DOI：
10.1111/jth.14147
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Li R
中科院分区：
文献类型：
--
作者：
Deng W;Voos KM;Li R
在最近的一项研究中，Butera 等人。提供了有趣的证据表明，将 A2 结构域中的 Cys1669-Cys1670 二硫键在其还原形式和氧化形式之间转换可以调节冯维勒布兰德因子 (VWF) 的活性，因此可能是其自身抑制机制的一部分 [1]。 VWF 是血液中的一种大的多聚体糖蛋白，主要由血管内皮细胞分泌，在止血、血栓形成和血栓炎症中起关键作用[2]。 VWF 多聚体的活性通常由其通过其 A1 结构域与血小板表面上的 GPIbα 的相互作用来定义。血浆 VWF 在低剪切条件下基本上保持不活跃状态，由于 VWF 单体内部和/或之间的相互作用而采用松散卷曲、浓缩的形状。这些相互作用可能掩盖了 A1 结构域，从而阻止 VWF 与血小板 GPIbα 结合。在固定或高剪切下，VWF 发生结构变化，增加 A1 的暴露，使其易于与 GPIbα 结合。激活结构变化或保持 A1 处于关闭状态的抑制相互作用的细节仍有待阐明。迄今为止，已经报道了 A1 和 D'-D3 组装体、A2 结构域以及 A1 结构域的 N 端和 C 端侧翼序列之间的三种结构域间抑制相互作用。在升高的剪切力或瑞斯托菌素的结合中产生的张力可能会干扰这些抑制性相互作用，并且已被提议将 VWF 转化为止血活性形式。在称为 2B 型冯维勒布兰德病的病理情况下，VWF 的“功能获得”或“抑制功能丧失”突变使循环 VWF 在低剪切条件下自发结合血小板 GPIbα。这些突变聚集在 A1 结构域内或周围 [2]，表明 A1 的暴露是 VWF 激活的核心步骤。在氧化环境（例如循环血液）中，游离硫醇会自发氧化。因此，通常认为 A2 结构域中的邻近半胱氨酸残基 Cys1669 和 Cys1670 形成二硫键，这确实已通过纯化 VWF 的早期生化分析以及 A2 的晶体结构进一步得到验证 [3, 4]。令人惊讶的是，布特拉等人。发现在重组表达的 A2 结构域的一小部分中，Cys1669 和 Cys1670 之一或两者被还原或与谷胱甘肽连接，并且在
In a recent study, Butera et al. provided intriguing evidence suggesting that switching the Cys1669-Cys1670 disulfide bond in the A2 domain between its reduced and oxidized forms could regulate the activity of von Willebrand factor (VWF) and therefore may be a part of its autoinhibitory mechanism [1]. VWF, a large multimeric glycoprotein in the blood secreted primarily from endothelial cells lining the blood vessels, critically mediates hemostasis, thrombosis, and thrombo-inflammation [2]. The activity of a VWF multimer is typically defined by its interaction, through its A1 domain, with GPIbα on the platelet surface. Plasma VWF remains largely inactive under low shear conditions, adopting a loosely coiled, condensed shape as a result of interactions within and/or between VWF monomers. These interactions presumably mask the A1 domain, which prevents VWF binding to platelet GPIbα. Upon immobilization or under high shear, VWF undergoes structural changes that increase the exposure of A1, making it accessible for GPIbα binding. The details of activating structural changes, or the inhibitory interactions keeping A1 in a closed state, remain to be elucidated. To-date, three inter-domain inhibitory interactions, between A1 and the D′-D3 assembly, the A2 domain, and both of the N-and C-terminal flanking sequences of the A1 domain, have been reported. The tensile force generated in elevated shear, or binding of ristocetin, likely interfere with these inhibitory interactions and have been proposed to transform VWF into the hemostatically active form. In a pathological scenario known as von Willebrand disease type 2B, a “gain-of-function” or “loss-of-inhibitoryfunction” mutation of VWF enables the circulating VWF to spontaneously bind platelet GPIbα under low shear conditions. These mutations are clustered in or around the A1 domain [2], suggesting that the exposure of A1 is a central step for the activation of VWF.In an oxidizing environment such as the circulating blood, free thiols are spontaneously oxidized. Thus, it is commonly assumed that the vicinal cysteine residues in the A2 domain, Cys1669 and Cys1670, form a disulfide bond, which has indeed been verified by early biochemical analysis of purified VWF and further by the crystal structure of A2 [3, 4]. Surprisingly, Butera et al. found that one or both of Cys1669 and Cys1670 are reduced or linked to glutathione in a minor portion of a recombinantly expressed A2 domain and in
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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：
13.6
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
通讯作者：
Hogg PJ
DOI：
10.1073/pnas.0903679106
发表时间：
2009-06-09
影响因子：
11.1
作者：
Zhang, Qing;Zhou, Yan-Feng;Springer, Timothy A.
通讯作者：
Springer, Timothy A.
影响因子：
2.9
作者：
MARTI, T;ROSSELET, SJ;WALSH, KA
通讯作者：
WALSH, KA