@article{9a9602da07d24e83947f7063f50f4ed8,
title = "An integrin αIIbβ3 intermediate affinity state mediates biomechanical platelet aggregation",
abstract = "Integrins are membrane receptors that mediate cell adhesion and mechanosensing. The structure–function relationship of integrins remains incompletely understood, despite the extensive studies carried out because of its importance to basic cell biology and translational medicine. Using a fluorescence dual biomembrane force probe, microfluidics and cone-and-plate rheometry, we applied precisely controlled mechanical stimulations to platelets and identified an intermediate state of integrin αIIbβ3 that is characterized by an ectodomain conformation, ligand affinity and bond lifetimes that are all intermediate between the well-known inactive and active states. This intermediate state is induced by ligand engagement of glycoprotein (GP) Ibα via a mechanosignalling pathway and potentiates the outside-in mechanosignalling of αIIbβ3 for further transition to the active state during integrin mechanical affinity maturation. Our work reveals distinct αIIbβ3 state transitions in response to biomechanical and biochemical stimuli, and identifies a role for the αIIbβ3 intermediate state in promoting biomechanical platelet aggregation.",
author = "Yunfeng Chen and Ju, {Lining Arnold} and Fangyuan Zhou and Jiexi Liao and Lingzhou Xue and Su, {Qian Peter} and Dayong Jin and Yuping Yuan and Hang Lu and Jackson, {Shaun P.} and Cheng Zhu",
note = "Funding Information: The authors thank A. Garcia (Georgia Tech), Z. Ruggeri (The Scripps Research Institute), B. Coller (Rockefeller University), P. Newman, R. Aster, J. Zhu and D. Bougie (BloodCenter of Wisconsin), W. Lam (Emory University) and F. Tovar Lopez (RMIT University) for providing precious reagents. The authors thank Y. Sakurai, D. Myer, Y. Qiu, R. Tran and J. Ciciliano from W. Lam lab (Georgia Tech) for the blood collection; R. Darbousset for support with platelet isolation and flow cytometry; A. Samson (WEHI) and J. MaClean (HRI) for cone-and-plate rheometry training; I. Alwis (USYD) for support with confocal microscopy; N. Court and E. Ilagan (USYD ANFF Research & Prototype Foundry) for advice on stenosis microchannel fabrication and characterization; S. Schoenwaelder (USYD), J. McFadyen (Baker Institute) and Z. Li (QUT) for helpful discussion. This work was supported by grants from the NIH (HL1320194, to C.Z.; R21EB020424, to H.L.), the NSF (DMS-1505256 and DMS-1811552, to L.X.), the NIDA (P50 DA039838, to L.X.), the NHMRC (APP1028564 and APP1048574, to S.P.J.), the Australian Research Council (LE120100043, to S.P.J.), the University of Technology Sydney{\textquoteright}s Grant for IBMD (to Q.P.S.), the Diabetes Australia Research Program General Grant (G179720), the University of Sydney Early-Career Researcher Kickstart Grant and Cardiovascular Initiative Catalyst Grant for Precision CV Medicine, the Royal College of Pathologists of Australasia Kanematsu research award and the Cardiac Society of Australia and New Zealand BAYER Young Investigator Research Grant (to L.A.J.). S.P.J. is an NHMRC Senior Principal Research Fellow. L.A.J. is an Australian Research Council DECRA fellow (DE190100609) and a former National Heart Foundation of Australia postdoctoral fellow (101798). Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = jul,
day = "1",
doi = "10.1038/s41563-019-0323-6",
language = "English (US)",
volume = "18",
pages = "760--769",
journal = "Nature Materials",
issn = "1476-1122",
publisher = "Nature Publishing Group",
number = "7",
}