Crystal structures of the noncatalytic domains of ADAMTS13 reveal multiple discontinuous exosites for von Willebrand factor
AUTOR(ES)
Akiyama, Masashi
FONTE
National Academy of Sciences
RESUMO
ADAMTS13 specifically cleaves plasma von Willebrand factor (VWF) and thereby controls VWF-mediated platelet thrombus formation. Severe deficiencies in ADAMTS13 can cause life-threatening thrombotic thrombocytopenic purpura. Here, we determined 2 crystal structures of ADAMTS13-DTCS (residues 287–685), an exosite-containing human ADAMTS13 fragment, at 2.6-Å and 2.8-Å resolution. The structures revealed folding similarities between the disintegrin-like (D) domain and the N-terminal portion of the cysteine-rich domain (designated the CA domain). The spacer (S) domain forms a globular functional unit with a 10-stranded β-sandwich fold that has multiple interaction sites with the CA domain. We expressed 25 structure-based mutants of ADAMTS13-MDTCS (residues 75–685) and measured their enzymatic activity. We identified 3 VWF-binding exosites on the linearly aligned discontinuous surfaces of the D, CA, and S domains traversing the W-shaped molecule. Since the MDTCS domains are conserved among ADAMTS family proteins, the structural framework of the multiple enzyme-substrate interactions identified in the ADAMTS13-VWF system provides the basis for a common substrate recognition mode in this class of proteinases.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2780749Documentos Relacionados
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