Shear tango: dance of the ADAMTS13/VWF complex

Abstract

ADAMTS13, the metalloprotease that regulates the size of von Willebrand factor (VWF), is critical in preventing microvascular platelet clumping, such as occurs in thrombotic thrombocytopenic purpura. The article in this issue of Blood by Gao et al addresses how these two proteins use multiple binding sites to facilitate proteolytic regulation of VWF.

A homology model of the ADAMTS13 metalloprotease (magenta) and disintegrin-like domains (cyan) is shown (MD) to provide a sense of scale, with active site Zn2+ ion (green) and 3 structural Ca2+ ions (gray) as spheres. The VWF A2 domain is predicted to consist of a 6-stranded β-sheet surrounded by 5 α-helices. Residues Tyr¹⁶⁰⁵-Met¹⁶⁰⁶ (side chains in red) are buried in strand β4. Exposure of this bond to ADAMTS13 requires substantial unfolding of domain A2; more distal segments that interact with specific domains of ADAMTS13 are labeled. The locations of these ADAMTS13 domains relative to the MD moiety are not known. Deletion of strand β5 through helix α4 (dispensable) has a minimal effect on the rate of substrate cleavage. Molecular graphics prepared with PyMOL (DeLano Scientific, Palo Alto, CA). See the complete figure in the article beginning on page 1713.