Molecular basis and cellular functions of vinculin-actin directional catch bonding

Venkat R. Chirasani, Mohammad Ashhar I. Khan, Juilee N. Malavade, Nikolay V. Dokholyan (), Brenton D. Hoffman () and Sharon L. Campbell ()
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Venkat R. Chirasani: University of North Carolina at Chapel Hill
Mohammad Ashhar I. Khan: University of North Carolina at Chapel Hill
Juilee N. Malavade: Duke University
Nikolay V. Dokholyan: Penn State College of Medicine
Brenton D. Hoffman: Duke University
Sharon L. Campbell: University of North Carolina at Chapel Hill

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract The ability of cells and tissues to respond differentially to mechanical forces applied in distinct directions is mediated by the ability of load-bearing proteins to preferentially maintain physical linkages in certain directions. However, the molecular basis and biological consequences of directional force-sensitive binding remain unclear. Vinculin (Vcn) is a load-bearing linker protein that exhibits directional catch bonding due to interactions between the Vcn tail domain (Vt) and filamentous (F)-actin. We developed a computational approach to predict Vcn residues involved in directional catch bonding and produced a set of associated Vcn variants with unaltered Vt structure, actin binding, or phospholipid interactions. Incorporation of the variants did not affect Vcn activation but reduced Vcn loading and altered exchange dynamics, consistent with the loss of directional catch bonding. Expression of Vcn variants perturbed the coordination of subcellular structures and cell migration, establishing key cellular functions for Vcn directional catch bonding.

Date: 2023
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DOI: 10.1038/s41467-023-43779-x

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