Diego Butera, Freda Passam, Lining Ju, Kristina M Cook, Heng Woon, Camilo Aponte-Santamaría, Elizabeth Gardiner, Amanda K Davis, Deirdre A Murphy, Agnieszka Bronowska, Brenda M Luken, Carsten Baldauf, Shaun Jackson, Robert Andrews, Frauke Gräter, Philip J Hogg
Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this "mechanopresentation" remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring...
February 2018: Science Advances