功能获得性血管性血友病因子疾病中突变引起的力诱导结合速率切换和调节
Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases.
作者信息
Kim Jongseong, Hudson Nathan E, Springer Timothy A
机构信息
Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115
出版信息
Proc Natl Acad Sci U S A. 2015 Apr 14;112(15):4648-53. doi: 10.1073/pnas.1501689112. Epub 2015 Mar 25.
Mutations in the ultralong vascular protein von Willebrand factor (VWF) cause the common human bleeding disorder, von Willebrand disease (VWD). The A1 domain in VWF binds to glycoprotein Ibα (GPIbα) on platelets, in a reaction triggered, in part, by alterations in flow during bleeding. Gain-of-function mutations in A1 and GPIbα in VWD suggest conformational regulation. We report that force application switches A1 and/or GPIbα to a second state with faster on-rate, providing a mechanism for activating VWF binding to platelets. Switching occurs near 10 pN, a force that also induces a state of the receptor-ligand complex with slower off-rate. Force greatly increases the effects of VWD mutations, explaining pathophysiology. Conversion of single molecule kon (s(-1)) to bulk phase kon (s(-1)M(-1)) and the kon and koff values extrapolated to zero force for the low-force pathways show remarkably good agreement with bulk-phase measurements.
超长血管蛋白血管性血友病因子（VWF）的突变会导致常见的人类出血性疾病——血管性血友病（VWD）。VWF中的A1结构域与血小板上的糖蛋白Ibα（GPIbα）结合，这一反应部分由出血时血流变化引发。VWD中A1和GPIbα的功能获得性突变提示存在构象调节。我们报告，施加力会将A1和/或GPIbα转换为结合速率更快的第二种状态，为激活VWF与血小板的结合提供了一种机制。转换发生在接近10皮牛的力时，该力还会诱导受体-配体复合物进入解离速率较慢的状态。力极大地增强了VWD突变的影响，解释了病理生理学机制。单分子结合速率常数kon（s⁻¹）转换为体相kon（s⁻¹M⁻¹），以及低力途径外推至零力时的kon和koff值与体相测量结果显示出非常好的一致性。
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