PMID- 27434669
OWN - NLM
STAT- MEDLINE
DCOM- 20171116
LR  - 20181113
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 5
DP  - 2016 Jul 19
TI  - Cooperative unfolding of distinctive mechanoreceptor domains transduces force 
      into signals.
LID - e15447 [pii]
LID - 10.7554/eLife.15447 [doi]
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 alpha subunit 
      (GPIbalpha), 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-GPIbalpha dissociation and unfolds the GPIbalpha 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-GPIbalpha 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.
FAU - Ju, Lining
AU  - Ju L
AD  - Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 
      Atlanta, United States.
AD  - Petit Institute for Bioengineering and Biosciences, Georgia Institute of 
      Technology, Atlanta, United States.
AD  - Heart Research Institute, Camperdown, Australia.
AD  - Charles Perkins Centre, The University of Sydney, Camperdown, Australia.
FAU - Chen, Yunfeng
AU  - Chen Y
AD  - Petit Institute for Bioengineering and Biosciences, Georgia Institute of 
      Technology, Atlanta, United States.
AD  - Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 
      Atlanta, United States.
FAU - Xue, Lingzhou
AU  - Xue L
AD  - Department of Statistics, The Pennsylvania State University, University Park, 
      United States.
FAU - Du, Xiaoping
AU  - Du X
AD  - Department of Pharmacology, College of Medicine, University of Illinois at 
      Chicago, Chicago, United States.
FAU - Zhu, Cheng
AU  - Zhu C
AUID- ORCID: 0000-0002-1718-565X
AD  - Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 
      Atlanta, United States.
AD  - Petit Institute for Bioengineering and Biosciences, Georgia Institute of 
      Technology, Atlanta, United States.
AD  - Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 
      Atlanta, United States.
LA  - eng
GR  - R01 HL062350/HL/NHLBI NIH HHS/United States
GR  - R01 HL080264/HL/NHLBI NIH HHS/United States
GR  - R01 HL125356/HL/NHLBI NIH HHS/United States
GR  - R01 HL132019/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20160719
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (Platelet Glycoprotein GPIb-IX Complex)
RN  - 0 (adhesion receptor)
RN  - 0 (von Willebrand Factor)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Blood Platelets/*physiology
MH  - Calcium/*metabolism
MH  - Humans
MH  - Mechanoreceptors/*metabolism
MH  - Platelet Glycoprotein GPIb-IX Complex/*metabolism
MH  - Protein Binding
MH  - Protein Folding
MH  - von Willebrand Factor/*metabolism
PMC - PMC5021522
OTO - NOTNLM
OT  - GPIb
OT  - biomembrane force probe
OT  - biophysics
OT  - calcium signaling
OT  - human
OT  - leucine rich repeat
OT  - mechanosensing
OT  - platelet
OT  - single molecule
OT  - structural biology
OT  - von willebrand disease
OT  - von willebrand factor
OT  - worm like chain
COIS- The authors declare that no competing interests exist.
EDAT- 2016/07/20 06:00
MHDA- 2017/11/29 06:00
PMCR- 2016/07/20
CRDT- 2016/07/20 06:00
PHST- 2016/02/23 00:00 [received]
PHST- 2016/07/18 00:00 [accepted]
PHST- 2016/07/20 06:00 [entrez]
PHST- 2016/07/20 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2016/07/20 00:00 [pmc-release]
AID - e15447 [pii]
AID - 15447 [pii]
AID - 10.7554/eLife.15447 [doi]
PST - epublish
SO  - Elife. 2016 Jul 19;5:e15447. doi: 10.7554/eLife.15447.