Conformational response of αIIbβ3 and αVβ3 integrins to force

Reza Kolasangiani; Khashayar Farzanian; Yunfeng Chen; Martin A Schwartz; Tamara C Bidone

doi:10.1016/j.str.2024.11.016

Conformational response of α_IIbβ₃ and α_Vβ₃ integrins to force

Structure. 2024 Dec 12:S0969-2126(24)00529-X. doi: 10.1016/j.str.2024.11.016. Online ahead of print.

Authors

Reza Kolasangiani¹, Khashayar Farzanian², Yunfeng Chen³, Martin A Schwartz⁴, Tamara C Bidone⁵

Affiliations

¹ Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA; Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, USA.
² Yale Cardiovascular Research Center, Department of Internal Medicine (Cardiology), Yale University, New Haven, CT, USA.
³ Department of Biochemistry and Molecular Biology and Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, USA.
⁴ Yale Cardiovascular Research Center, Department of Internal Medicine (Cardiology), Yale University, New Haven, CT, USA; Department of Cell Biology, Yale University, New Haven, CT, USA; Department of Biomedical Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT, USA.
⁵ Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA; Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, USA; Department of Biochemistry, University of Utah, Salt Lake City, UT, USA; Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT, USA. Electronic address: [email protected].

PMID: 39706199
DOI: 10.1016/j.str.2024.11.016

Abstract

As major adhesion receptors, integrins transmit biochemical and mechanical signals across the plasma membrane. These functions are regulated by transitions between bent and extended conformations and modulated by force. To understand how force on integrins mediates cellular mechanosensing, we compared two highly homologous integrins, α_IIbβ₃ and α_Vβ₃. These integrins, expressed in circulating platelets vs. solid tissues, respectively, share the β₃ subunit, bind similar ligands and have similar bent and extended conformations. Here, we report that in cells expressing equivalent levels of each integrin, α_IIbβ₃ mediates spreading on softer substrates than α_Vβ₃. These effects correlate with differences in structural dynamics of the two integrins under force. All-atom simulations show that α_IIbβ₃ is more flexible than α_Vβ₃ due to correlated residue motions within the α subunit domains. Single molecule measurements confirm that α_IIbβ₃ extends faster than α_Vβ₃. These results reveal a fundamental relationship between protein function and structural dynamics in cell mechanosensing.

Keywords: biomembrane force probe; integrins; mechanosensing; molecular conformational changes; molecular dynamics simulations; protein structure and function; α(IIb)β(3); α(V)β(3).