Kim H J, Xu Y, Petri A, Vanhoorelbeke K, Crawley J T B, Emsley J
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK.
Department of Immunology and Inflammation, Imperial College London, London, UK.
Sci Adv. 2021 Apr 16;7(16). doi: 10.1126/sciadv.abg4403. Print 2021 Apr.
ADAMTS13 is a plasma metalloprotease that is essential for the regulation of von Willebrand factor (VWF) function, mediator of platelet recruitment to sites of blood vessel damage. ADAMTS13 function is dynamically regulated by structural changes induced by VWF binding that convert it from a latent to active conformation. ADAMTS13 global latency is manifest by the interaction of its C-terminal CUB1-2 domains with its central Spacer domain. We resolved the crystal structure of the ADAMTS13 CUB1-2 domains revealing a previously unreported configuration for the tandem CUB domains. Docking simulations between the CUB1-2 domains with the Spacer domain in combination with enzyme kinetic functional characterization of ADAMTS13 CUB domain mutants enabled the mapping of the CUB1-2 domain site that binds the Spacer domain. Together, these data reveal the molecular basis of the ADAMTS13 Spacer-CUB interaction and the control of ADAMTS13 global latency.
ADAMTS13是一种血浆金属蛋白酶，对于血管性血友病因子（VWF）功能的调节至关重要，VWF是血小板募集到血管损伤部位的介质。ADAMTS13的功能通过VWF结合诱导的结构变化而动态调节，这种变化将其从潜伏构象转变为活性构象。ADAMTS13的整体潜伏性表现为其C末端CUB1-2结构域与其中央间隔结构域的相互作用。我们解析了ADAMTS13 CUB1-2结构域的晶体结构，揭示了串联CUB结构域以前未报道的构型。CUB1-2结构域与间隔结构域之间的对接模拟，结合ADAMTS13 CUB结构域突变体的酶动力学功能表征，使得能够绘制出与间隔结构域结合的CUB1-2结构域位点。这些数据共同揭示了ADAMTS13间隔-CUB相互作用的分子基础以及ADAMTS13整体潜伏性的控制机制。
