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Platelets use receptor glycoprotein Ib (GPIb), specifically its \u03b1 subunit (GPIb\u03b1), 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\u2013GPIb\u03b1 dissociation and unfolds the GPIb\u03b1 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 Ca2+ signal whereas MSD unfolding affects the type of Ca2+ signal. Therefore, LRRD and MSD are analog and digital force transducers, respectively. The &gt;30 nm macroglycopeptide separating the two domains transmits force on the VWF\u2013GPIb\u03b1 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.<\/jats:p>","DOI":"10.7554\/elife.15447","type":"journal-article","created":{"date-parts":[[2016,7,19]],"date-time":"2016-07-19T07:59:44Z","timestamp":1468915184000},"source":"Crossref","is-referenced-by-count":84,"title":["Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals"],"prefix":"10.7554","volume":"5","author":[{"given":"Lining","family":"Ju","sequence":"first","affiliation":[{"name":"Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, United States"},{"name":"Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, United States"},{"name":"Heart Research Institute, Camperdown, Australia"},{"name":"Charles Perkins Centre, The University of Sydney, Camperdown, 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