Journal
BLOOD
Volume 115, Issue 23, Pages 4910-4913Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-12-257949
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Funding
- British Heart Foundation [RG/02/008, RG/06/007]
- Biotechnology and Biological Sciences Research Council
- BBSRC [BB/E012132/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E012132/1] Funding Source: researchfish
- British Heart Foundation [RG/06/007/22029] Funding Source: researchfish
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The von Willebrand factor (VWF) A2 crystal structure has revealed the presence of a rare vicinal disulfide bond between C1669 and C1670, predicted to influence domain unfolding required for proteolysis by ADAMTS13. We prepared VWF A2 domain fragments with (A2-VicCC, residues 1473-1670) and without the vicinal disulfide bond (A2-Delta CC, residues 1473-1668). Compared with A2-Delta CC, A2-VicCC exhibited impaired proteolysis and also reduced binding to ADAMTS13. Circular dichroism studies revealed that A2-VicCC was more resistant to thermal unfolding than A2-Delta CC. Mutagenesis of C1669/C1670 in full-length VWF resulted in markedly increased susceptibility to cleavage by ADAMTS13, confirming the important role of the paired vicinal cysteines in VWF A2 domain stabilization. (Blood. 2010;115(23):4910-4913)
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