A model of the proposed mechanosensing mechanism of GPIb-IX. We found in this study that the juxtamembrane MSD in GPIbα is folded, and it unfolds upon VWF-mediated pulling. Our results suggest that on the cell surface, the juxtamembrane MSD in GPIbα is folded in the absence of shear flow (left panel). VWF binding under shear to the N-terminal domain of GPIbα induces unfolding of MSD, and subsequently a conformational change in the adjacent extracellular domains of GPIbβ and GPIX, which sends in a signal across the platelet membrane (right).