Title : Crystal structures of the noncatalytic
domains of
ADAMTS13 reveal multiple discontinuous
exosites for
von Willebrand factor
Abstract :
- 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-A and 2.8-A resolution
- The structures revealed folding similarities between the disintegrin-like (D) domain and the N-terminal portion of the cysteine-rich domain (designated the C(A) domain )
- The spacer (S) domain forms a globular functional unit with a 10-stranded beta-sandwich fold that has multiple interaction sites with the C(A) 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, C(A), 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