Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals

Lining Ju, Yunfeng Chen, Lingzhou Xue, Xiaoping Du, Cheng Zhu

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 elicits catch bonds to slow VWF–GPIbα dissociation 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 Ca2+ signal whereas MSD unfolding affects the type of Ca2+ 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–GPIbα 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.

Original languageEnglish (US)
Article numbere15447
JournaleLife
Volume5
Issue numberJULY
DOIs
StatePublished - Jul 19 2016

Fingerprint

Mechanoreceptors
Platelet Glycoprotein GPIb-IX Complex
Leucine
Platelets
Mechanical Phenomena
Blood Platelets
Biophysics
von Willebrand Factor
Transducers
Blood
Proteins

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ju, Lining ; Chen, Yunfeng ; Xue, Lingzhou ; Du, Xiaoping ; Zhu, Cheng. / Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals. In: eLife. 2016 ; Vol. 5, No. JULY.
@article{4d15993d0d83419c82769fec65ee31ef,
title = "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 elicits catch bonds to slow VWF–GPIbα dissociation 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 Ca2+ signal whereas MSD unfolding affects the type of Ca2+ 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–GPIbα 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.",
author = "Lining Ju and Yunfeng Chen and Lingzhou Xue and Xiaoping Du and Cheng Zhu",
year = "2016",
month = "7",
day = "19",
doi = "10.7554/eLife.15447",
language = "English (US)",
volume = "5",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
number = "JULY",

}

Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals. / Ju, Lining; Chen, Yunfeng; Xue, Lingzhou; Du, Xiaoping; Zhu, Cheng.

In: eLife, Vol. 5, No. JULY, e15447, 19.07.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals

AU - Ju, Lining

AU - Chen, Yunfeng

AU - Xue, Lingzhou

AU - Du, Xiaoping

AU - Zhu, Cheng

PY - 2016/7/19

Y1 - 2016/7/19

N2 - 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 elicits catch bonds to slow VWF–GPIbα dissociation 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 Ca2+ signal whereas MSD unfolding affects the type of Ca2+ 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–GPIbα 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.

AB - 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 elicits catch bonds to slow VWF–GPIbα dissociation 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 Ca2+ signal whereas MSD unfolding affects the type of Ca2+ 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–GPIbα 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.

UR - http://www.scopus.com/inward/record.url?scp=84988531523&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84988531523&partnerID=8YFLogxK

U2 - 10.7554/eLife.15447

DO - 10.7554/eLife.15447

M3 - Article

C2 - 27434669

AN - SCOPUS:84988531523

VL - 5

JO - eLife

JF - eLife

SN - 2050-084X

IS - JULY

M1 - e15447

ER -