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 α subunit (GPIbα), to signal as they tether and translocate on von Willebrand factor (VWF) of injured arterial surfaces against blood flow. Force slows VWF-GPIbα dissociation (catch bond) and unfolds the GPIbα 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 Ca2+ on a single platelet in real time, revealing that LRRD unfolding intensifies the Ca2+ signal analogously whereas MSD unfolding determines the Ca2+ type digitally. The >30nm macroglycopeptide separating the two domains transmits VWF-GPIbα bond lifetime prolonged by LRRD unfolding to enhance MSD unfolding cooperatively at an optimal force, which may serve as a design principle for a generic mechanosensory machine.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (Grant HL132019)
- Cheng Zhu
Diabetes Australia (IRMA G179720)
- Lining Ju
University of Sydney (2016 Sydney Medical School ECR Kickstart Grant)
- Lining Ju
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Human RBCs and platelets for BFP experiments were collected abiding a protocol (#H12354) approved by the Institute Review Broad of Georgia Institute of Technology. Informed consent was obtained from each blood donor.
Copyright
© 2016, Ju et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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