Publication highlights

Chemical reactions are initiated by an energy source that can be provided by heat, electric current or light, and are generally governed by the rules of thermodynamics. Mechanical forces are an alternative means of activating chemical reactions, often steering reaction pathways that result in products different from those obtained under thermodynamic control. In this work, researchers from the Crick demonstrated that mechanical forces activate chemical reactions that are chemically forbidden, such as the reduction of an individual protein disulfide bond by an inorganic sulfur-oxyanion. Occurring within the core of a protein with a physiological mechanical role, the force-unlocked reactivity has a direct impact on protein elasticity.

Researchers at the Crick and King’s College London have discovered that how soft or rigid proteins are in certain regions can dictate how fast or slow they enter the nucleus. By tracking the movement of proteins in single cells, they showed that, in proteins of the same size and composition of amino acids, mechanical stability near a protein's nuclear-localisation sequence influenced how fast or slow they could cross. Adding a soft tag near the sequence on stiffer proteins helped them enter the nucleus more easily, which was tested by tagging MRTF transcription factor with a soft tag. This could be a useful tool for delivering drugs to the nucleus more quickly, or tagging transcription factors to increase the activity of certain genes.

Understanding how proteins fold has been a central question in biophysics for decades. Machine learning-based approaches have recently made great progress in predicting protein structures, but the dynamics of folding required to achieve these structures are more challenging to predict, generally requiring experimental observation. Using single-molecule force spectroscopy, the Garcia-Manyes lab has developed a new method to watch a single protein fold for days rather than hours, revealing rare excursions into configurations that were previously hidden from observation. They focused on a segment of the protein talin, which is involved in sensing and responding to external forces applied to cells, and by also doing measurements in the presence of one of talin’s binding partners, vinculin, they were also able to probe the biological relevance of the folding states, including those that were misfolded, that they observed.

Given that the trapping of proteins in metastable high-energy states is one of the hurdles in the design of novel proteins, the detailed characterisation of such states made possible by this approach may help improve computational methods for protein design, as well as potentially providing insights into the range of diseases caused by protein misfolding. It also has implications for our understanding of many force-induced gene expression programmes, ultimately related to cell function.