의생명시스템학부

제목: Crytstal structure of ADAMTS13 reveals its role in global latency

내용:

ADAMTS13 is a plasma metalloprotease that is essential for the regulation of von Willebrand factor (VWF) function, an essential 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 N-terminal domain. We resolved the crystal structure of the ADAMTS13 N-terminal, metalloprotease to Spacer domain, and C-terminal, CUB1-2 domains. The binding of the ADAMTS13 to VWF allosterically activates the metalloprotease domain to facilitate proteolysis. The crystal structure of the ADAMTS13 N-terminal domains revealed that the metalloprotease domain exhibits a latent conformation in which the active-site cleft is occluded supporting the requirement for an allosteric change to enable accommodation of the substrate. The C-terminal revealed a novel 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 exosite 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.