University of Cambridge > Talks.cam > Biophysical Seminars > Self-entangled misfolded structures are the molecular bridge connecting synonymous mutations to long-timescale changes in protein structure and function

Self-entangled misfolded structures are the molecular bridge connecting synonymous mutations to long-timescale changes in protein structure and function

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Synonymous mutations, which alter an mRNA sequence but not the encoded protein sequence, have been found to alter the long-timescale function of proteins, including the specific activity of enzymes and the ability of proteins to form oligomers. It is unknown how synonymous mutations lead to such changes in protein structure and function, and why these altered structures are not fixed by the proteostasis machinery. Here, we address this gap in our knowledge using a combination of multi-scale molecular modeling, high-throughput simulations, and meta-analysis of the literature. We first show that across the E. coli cytosolic proteome many nascent proteins populate subpopulations of long-lived kinetically trapped states that are near native like but likely have reduced functionality due to localized misfolding. We then show, using coarse-grained simulations, that these near-native misfolded states can bypass E. coli chaperones because they expose similar hydrophobic surface area as the native state. We then demonstrate, through a meta-analysis of the experimental literature, that in vitro it is common for appreciable subpopulations of proteins to be misfolded, non-functional but bypass chaperones. Finally, using multi-scale modeling, we demonstrate that population shifts in kinetically trapped entangled states brought about by synonymous mutations explain the resulting changes in the specific activity of proteins. These studies indicate that there is a fourth fate of proteins in cells – near-native, soluble misfolded states that bypass the proteostasis machinery whose populations are influenced by changes in translation elongation speed. These results motivate future experimental efforts to demonstrate the existence of these entangled structures, and the influence this ‘dark proteome’ has on phenotype

This talk is part of the Biophysical Seminars series.

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