Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals.

ABSTRACT: How cells sense their mechanical environment and transduce forces into biochemical signals is a crucial yet unresolved question in mechanobiology. Platelets use receptor glycoprotein Ib (GPIb), specifically its ? subunit (GPIb?), to signal as they tether and translocate on von Willebrand factor (VWF) of injured arterial surfaces against blood flow. Force elicits catch bonds to slow VWF-GPIb? dissociation and unfolds the GPIb? leucine-rich repeat domain (LRRD) and juxtamembrane mechanosensitive domain (MSD). How these mechanical processes trigger biochemical signals remains unknown. Here we analyze these extracellular events and the resulting intracellular Ca(2+) on a single platelet in real time, revealing that LRRD unfolding intensifies Ca(2+) signal whereas MSD unfolding affects the type of Ca(2+) signal. Therefore, LRRD and MSD are analog and digital force transducers, respectively. The >30 nm macroglycopeptide separating the two domains transmits force on the VWF-GPIb? bond (whose lifetime is prolonged by LRRD unfolding) to the MSD to enhance its unfolding, resulting in unfolding cooperativity at an optimal force. These elements may provide design principles for a generic mechanosensory protein machine.

SUBMITTER: Ju L 

PROVIDER: S-EPMC5021522 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature