作者：Xubin; Xie; Ying; Fang; Jianhua; Wuvwfproteinunfoldingsmdadmats13of
摘要：At the vascular injury sites,the ultra-large (UL) multimeric von willebrand Factor (VWF) is released in response to physiological and pathophysiological stimuli,and mediates platelet adhesion,aggregation,and cross-linking to maintain hemostasis.This UL-VWF is specifically cleaved by ADAMTS13(A Disintegrin And Metalloprotease with a ThromboSpondintype-1 motif,member 13)to prevent microvascular thrombosis.Each VWF monomer consists of five types of repeat domains in the order of D1-D2-D’-D3-A1-A2-A3-D4-C1-C2-C3-C4-C5-C6-CK,in which the A2 domain contains the ADAMTS13cleavage site(Tyr1605-Met1606),exposure of which requires mechanical or chemical stimuli.Under flows,fluid shear stress regulates VWF degradation and size distribution through opening the A2 domain and exposing its cleavage site for ADAMTS13.VWF A2 domain contains a C-terminal vicinal disulfide bond,a calcium binding sites,and a flexibleα4-less-loop.These unique structure features together make A2 more sensitive to mechanical signal than other VWF A subdomains,i.e.A1 and A3 domains.It is believed that A2 is first bound with and then cleaved by ADAMTS13,together with force-induced conformation transformation.To reveal molecular basis of this two-step model of VWF hydrolyzation by ADAMTS13,we here examined stretch-induced unfolding processes of VWF A2 domain in more detail by Steered molecular dynamics(SMD)simulations,with the use of crystal structure of VWF A2(PDB ID 3GXB),and observed that there were multiple quasi-stable conformations of stretched A2 until itsβ4-strand and a3-helix were pulled away the central hydrophobic core and the cleavage sites were fully accessible to solvent.Our MD simulation data showed that,in unfolding,at first,the cleavage site residue Tyr1605 was exposed partially and binding sites for Spacer domain of ADAMTS13 were exposed to a high level whenα6-helix was separated from A2 body;then,withβ6-strand and a5-helix been pulled away,the binding sites for Cysrich domain of ADAMTS13 was exposed completely while the exposure de
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