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The role of single-protein elasticity in mechanobiology

Nature Reviews Materials volume 8, pages 10–24 (2023)Cite this article

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Abstract

In addition to biochemical signals and genetic considerations, mechanical forces are rapidly emerging as a master regulator of human physiology. However, the molecular mechanisms that regulate force-induced functionalities across a wide range of scales, encompassing the cell, tissue or organ levels, are not well understood in comparison. With the advent, development and refining of single-molecule nanomechanical techniques that enable the conformational dynamics of individual proteins under the effect of a calibrated force to be probed, we have begun to acquire a comprehensive knowledge of the diverse physicochemical principles that regulate the elasticity of single proteins. Here, we review the major advances underpinning our current understanding of how the elasticity of single proteins regulates mechanosensing and mechanotransduction. We discuss the present limitations and future challenges of this prolific and burgeoning field.

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Fig. 1: Single-molecule force spectroscopy techniques used to map the (un)folding energy landscape of a protein under force.
Fig. 2: Nanomechanical regulation of the cell matrix and the focal adhesion hub.
Fig. 3: Mechanical force regulates the nature of interactions within the cytoskeleton and between cells.
Fig. 4: Muscle nanomechanics.
Fig. 5: Integrating single-molecule experiments into cells.

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Acknowledgements

This work was supported in part by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001002), the UK Medical Research Council (FC001002) and the Wellcome Trust (FC001002). A.E.M.B. is the recipient of a Sir Henry Wellcome fellowship (210887/Z/18/Z). This work was supported by the European Commission (Mechanocontrol, grant agreement 731957), an EPSRC Fellowship (K00641X/1), a BBSRC sLOLA (BB/V003518/1), a Leverhulme Trust Research Leadership Award (RL 2016-015), a Wellcome Trust Investigator Award (212218/Z/18/Z) and a Royal Society Wolfson Fellowship (RSWF/R3/183006) to S.G.-M.

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  1. Department of Physics, Randall Centre for Cell and Molecular Biophysics, Centre for the Physical Science of Life and London Centre for Nanotechnology, King’s College London, Strand, London, UK

    Amy E. M. Beedle & Sergi Garcia-Manyes

  2. Institute for Bioengineering of Catalonia (IBEC), the Barcelona Institute of Technology (BIST), Barcelona, Spain

    Amy E. M. Beedle

  3. Single Molecule Mechanobiology Laboratory, The Francis Crick Institute, London, UK

    Sergi Garcia-Manyes

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Glossary

Mechanosensing

A broad term encompassing the mechanisms by which cells can sense mechanical forces from the environment.

Mechanotransduction

The process by which cells convert a mechanical stimulus into a biochemical signal.

Persistence length

Measure of the protein stiffness. Characteristic length beyond which thermal forces randomize the direction of the protein polymer.

Domains

Functional or structural unit within a large protein.

Proline mutation

The insertion of a bulky proline amino acid into the mechanical clamp region of the protein is a method of disrupting the hydrogen bonds and lowering the force required to mechanically unfold a protein.

Catch bond

A bond whose lifetime increases when subjected to mechanical force.

Slip bond

A bond whose lifetime decreases when subjected to mechanical force.

Isoform

Member of a family of highly similar proteins encoded by the same gene or gene family. Some isoforms have the same function, whereas others have unique functions.

Conserved

Identical or similar sequences across species or genomes, which have been maintained through natural selection.

Sarcomere

Smallest functional unit of striated muscle tissue. Each is composed of protein filaments that slide past each other upon muscle contraction and relaxation.

Alternatively spliced

Process during gene expression that allows a single gene to code for multiple proteins.

Z- and M-lines

In a sarcomere, two Z-lines define its boundaries. The M-line runs down the centre of the sarcomere, through the middle of the myosin filaments.

Post-translational modifications

Chemical modifications, often in the amino acid side chains of a protein, that occur after translation. In the context of protein mechanics, post-translational modifications might affect the protein’s mechanical stability and its folding dynamics.

Chaperone

A protein whose function is to assist in the folding or unfolding process of another (client) protein.

SecM-stalled ribosomes

SecM is a bacterial protein that stalls while it is being made at the ribosome.

Translocation

Process by which a molecule (protein) threads through a narrow (biological) pore.

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Beedle, A.E.M., Garcia-Manyes, S. The role of single-protein elasticity in mechanobiology. Nat Rev Mater 8, 10–24 (2023). https://doi.org/10.1038/s41578-022-00488-z

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