title: Modeling ADAMTS13-von Willebrand factor interaction: Implications for oxidative stress-related cardiovascular diseases and type 2A von Willebrand disease.
abstract: The haemostatic potential of von Willebrand factor, a glycoprotein expressed by endothelial cells as ultra-large polymers (UL-vWF)(1), increases with its length, which in turn is regulated proteolytically by ADAMTS13, a zinc-metalloprotease selectively cleaving vWF at the Tyr1605-Met1606 bond. We have recently shown that in vitro oxidation of Met1606, under conditions mimicking those found in diseases characterized by high oxidative stress, severely impairs proteolysis by ADAMTS13, with a resulting pro-thrombotic effect caused by the accumulation of UL-vWF species. Conversely, Val1607Asp mutation, found in vWF from patients with type 2A von Willebrand disease, accelerates proteolysis of vWF, with a final hemorrhagic effect. Considering the physio-pathological importance of ADAMTS13-vWF interaction and the absence of experimental structural data, here we produced by homology modeling techniques a three-dimensional model of ADAMTS13 metalloprotease domain (M13). Thereafter, the vWF(1604-1607) peptide, containing the cleavable Tyr1605-Met1606 bond, was manually docked into the protease active site and the resulting model complex provided us key information for interpreting on structural grounds the variable effects that chemical modifications/mutations in vWF have on proteolysis by ADAMTS13.
authors.affiliation: Laboratory of Protein Chemistry, Department of Pharmaceutical Sciences, University of Padua, Padua, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Pozzi
authors.forename: Stefano
authors.initials: S
authors.lastname: Lancellotti
authors.forename: Raimondo
authors.initials: R
authors.lastname: De Cristofaro
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Filippis
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000071097:ADAMTS1 Protein; D000595:Amino Acid Sequence; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D016415:Sequence Alignment; D056728:von Willebrand Disease, Type 2 / Q000201:enzymology / Q000378:metabolism*; D014841:von Willebrand Factor / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human