Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/179944
Title: Force-regulated spontaneous conformational changes of integrins α5β1 and αVβ3
Authors: Chen, Yunfeng
Li, Zhenhai
Kong, Fang
Ju, Arnold Lining
Zhu, Cheng
Keywords: Medicine, Health and Life Sciences
Issue Date: 2024
Source: Chen, Y., Li, Z., Kong, F., Ju, A. L. & Zhu, C. (2024). Force-regulated spontaneous conformational changes of integrins α5β1 and αVβ3. ACS Nano, 18(1), 299-313. https://dx.doi.org/10.1021/acsnano.3c06253
Journal: ACS Nano 
Abstract: Integrins are cell surface nanosized receptors crucial for cell motility and mechanosensing of the extracellular environment, which are often targeted for the development of biomaterials and nanomedicines. As a key feature of integrins, their activity, structure and behavior are highly mechanosensitive, which are regulated by mechanical forces down to pico-Newton scale. Using single-molecule biomechanical approaches, we compared the force-modulated ectodomain bending/unbending conformational changes of two integrin species, α5β1 and αVβ3. It was found that the conformation of integrin α5β1 is determined by a threshold head-to-tail tension. By comparison, integrin αVβ3 exhibits bistability even without force and can spontaneously transition between the bent and extended conformations with an apparent transition time under a wide range of forces. Molecular dynamics simulations observed almost concurrent disruption of ∼2 hydrogen bonds during integrin α5β1 unbending, but consecutive disruption of ∼7 hydrogen bonds during integrin αVβ3 unbending. Accordingly, we constructed a canonical energy landscape for integrin α5β1 with a single energy well that traps the integrin in the bent state until sufficient force tilts the energy landscape to allow the conformational transition. In contrast, the energy landscape of integrin αVβ3 conformational changes was constructed with hexa-stable intermediate states and intermediate energy barriers that segregate the conformational change process into multiple small steps. Our study elucidates the different biomechanical inner workings of integrins α5β1 and αVβ3 at the submolecular level, helps understand their mechanosignaling processes and how their respective functions are facilitated by their distinctive mechanosensitivities, and provides useful design principles for the engineering of protein-based biomechanical nanomachines.
URI: https://hdl.handle.net/10356/179944
ISSN: 1936-0851
DOI: 10.1021/acsnano.3c06253
Schools: School of Biological Sciences 
Rights: © 2023 The Authors. Published by American Chemical Society. This article is licensed under CC-BY 4.0.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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