Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals

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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.

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Lining Ju

Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, United States

Competing interests
The authors declare that no competing interests exist.
Yunfeng Chen

Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, United States

Competing interests
The authors declare that no competing interests exist.
Lingzhou Xue

Department of Statistics, Pennsylvania State University, University Park, United States

Competing interests
The authors declare that no competing interests exist.
Xiaoping Du

Department of Pharmacology, University of Illinois at Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Cheng Zhu

Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, United States

For correspondence
cheng.zhu@bme.gatech.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1718-565X

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

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.