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 Blood, 24 September 2009, Vol. 114, No. 13, pp. 2819-2828.
Prepublished online as a Blood First Edition Paper on July 8, 2009; DOI 10.1182/blood-2009-05-224915.

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THROMBOSIS AND HEMOSTASIS

A novel binding site for ADAMTS13 constitutively exposed on the surface of globular VWF

Sara Zanardelli1, Alain C. K. Chion1, Evelyn Groot2, Peter J. Lenting2, Thomas A. J. McKinnon1, Mike A. Laffan1, Michelle Tseng1, and David A. Lane1

1 Department of Haematology, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom; and 2 Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands

ADAMTS13 metalloprotease regulates the multimeric size of von Willebrand factor (VWF) by cleaving the Tyr1605-Met1606 bond in the VWF A2 domain. The mechanisms of VWF recognition by ADAMTS13 have yet to be fully resolved. Most studies have focused on the role of exosites within the VWF A2 domain, involved in interaction with the ADAMTS13 spacer domain. In the present study, we expressed different C-terminal domain VWF fragments and evaluated their binding to ADAMTS13 and its truncated mutants, MDTCS and del(TSP5-CUB). Using plate binding assay and surface plasmon resonance, we identified a novel ADAMTS13 binding site (KD ~ 86 nM) in the region of VWF spanning residues 1874 to 2813, which includes the VWF D4 domain and that interacts with the C-terminal domains of ADAMTS13. We show that the interaction occurs even when VWF is in static conditions, assumed to be globular and where the VWF A2 domain is hidden. We demonstrate that C-terminal VWF fragments, as well as an antibody specifically directed toward the VWF D4 domain, inhibit VWF proteolysis by ADAMTS13 under shear conditions. We propose that this novel VWF C-terminal binding site may participate as the initial step of a multistep interaction ultimately leading to proteolysis of VWF by ADAMTS13.


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