From the Department of Bioengineering, Rice University, Houston, Texas 77005.
J Biol Chem. 2013 Nov 15;288(46):33118-23. doi: 10.1074/jbc.M113.487413. Epub 2013 Oct 4.
Shiga toxin (Stx) produced by enterohemorrhagic Escherichia coli causes diarrhea-associated hemolytic-uremic syndrome (DHUS), a severe renal thrombotic microangiopathy. We investigated the interaction between Stx and von Willebrand Factor (VWF), a multimeric plasma glycoprotein that mediates platelet adhesion, activation, and aggregation. Stx bound to ultra-large VWF (ULVWF) secreted from and anchored to stimulated human umbilical vein endothelial cells, as well as to immobilized VWF-rich human umbilical vein endothelial cell supernatant. This Stx binding was localized to the A1 and A2 domain of VWF monomeric subunits and reduced the rate of ADAMTS-13-mediated cleavage of the Tyr(1605)-Met(1606) peptide bond in the A2 domain. Stx-VWF interaction and the associated delay in ADAMTS-13-mediated cleavage of VWF may contribute to the pathophysiology of DHUS.
志贺毒素（Stx）由产志贺毒素大肠埃希菌产生，可引起腹泻相关溶血尿毒综合征（DHUS），即一种严重的肾血栓性微血管病。我们研究了 Stx 与血管性血友病因子（VWF）之间的相互作用，VWF 是一种介导血小板黏附、活化和聚集的多聚体血浆糖蛋白。Stx 可与从受刺激的人脐静脉内皮细胞分泌和锚定的超大 VWF（ULVWF）结合，也可与固定化富含 VWF 的人脐静脉内皮细胞上清液结合。这种 Stx 结合定位于 VWF 单体亚基的 A1 和 A2 结构域，并降低 ADAMTS-13 介导的 A2 结构域中 Tyr（1605）-Met（1606）肽键裂解的速度。Stx-VWF 相互作用以及 ADAMTS-13 介导的 VWF 裂解的相关延迟可能导致 DHUS 的病理生理学变化。
