Crystal structure of the exosite-containing fragment of human ADAMTS13 (P475S mutant)
[ATS13_HUMAN] Defects in ADAMTS13 are the cause of thrombotic thrombocytopenic purpura congenital (TTP) [MIM:274150]; also known as Upshaw-Schulman syndrome (USS). A hematologic disease characterized by hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and non-focal neurologic findings, decreased renal function and fever.                   
[ATS13_HUMAN] Cleaves the vWF multimers in plasma into smaller forms.
Publication Abstract from PubMed
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.
Crystal structures of the noncatalytic domains of ADAMTS13 reveal multiple discontinuous exosites for von Willebrand factor.,Akiyama M, Takeda S, Kokame K, Takagi J, Miyata T Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19274-9. Epub 2009 Oct 30. PMID:19880749
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.