ADAMTS13 structure in normal and disease states

正常和疾病状态下的 ADAMTS13 结构

• 批准号: 2448915
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2448915
• 关键词: ADAMTS13; structure; normal; disease; states

Blood clotting requires recruitment of platelets (specialised blood cells) to the site of injury as one of the first (of many) events that prevents bleeding. This process is highly dependent upon a protein known as von Willebrand factor (VWF) that circulates in blood which is regulated by ADAMTS13 (A Disintegrin-like And Metalloprotease with ThromboSpondin type I repeats, member 13). Clinically, human deficiency in VWF is the most common inherited bleeding disorder, whereas people with ADAMTS13 deficiency suffer from a life-threatening thrombotic disorder with a ~90% mortality rate. ADAMTS13 is a very highly specific proteolytic enzyme that cleaves only one protein (VWF) and does so at just a single site, and even then, only under very specific conditions of blood flow. The metalloprotease domain of this enzyme contains the active site that cleaves VWF and how ADAMTS13 recognises and cleaves VWF so specifically remains unclear. To understand this at a molecular level, we will ascertain the structure of whole ADAMTS13, both in free forms and in stabilising complexes with specific antibody fragments using cryo-electron microscopy. We will also analyse hereditary mutations in the ADAMTS13 gene linked to paediatric stroke and thrombotic thrombocytopenic purpura.

凝血需要将血小板(特殊的血细胞)重新聚集到损伤部位，这是防止出血的第一个(许多)事件之一。这一过程高度依赖于一种名为von Willebrand因子(VWF)的蛋白质，该蛋白质在血液中循环，受ADAMTS13(具有凝血酶反应蛋白I型重复的去整合素样和金属蛋白酶，成员13)调节。在临床上，人类VWF缺陷是最常见的遗传性出血性疾病，而ADAMTS13缺陷者患有一种危及生命的血栓性疾病，死亡率约为90%。ADAMTS13是一种高度特异的蛋白水解酶，它只分解一种蛋白质(VWF)，而且只在一个位置上分解，即使这样，也只有在非常特殊的血流条件下才能分解。这种酶的金属蛋白酶域包含切割VWF的活性部位，以及ADAMTS13如何识别和切割VWF，目前尚不清楚。为了在分子水平上理解这一点，我们将确定整个ADAMTS13的结构，包括游离形式和使用冷冻电子显微镜稳定与特定抗体片段的复合体。我们还将分析ADAMTS13基因的遗传突变与儿童中风和血栓性血小板减少性紫癜有关。