Hidden information on protein function in censuses of proteome foldedness

Dezerae Cox, Ching-Seng Ang, Nadinath B. Nillegoda, Gavin E. Reid and Danny M. Hatters ()
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Dezerae Cox: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
Ching-Seng Ang: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
Nadinath B. Nillegoda: Australian Regenerative Medicine Institute, Monash University
Gavin E. Reid: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
Danny M. Hatters: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Methods that assay protein foldedness with proteomics have generated censuses of apparent protein folding stabilities in biological milieu. However, different censuses poorly correlate with each other. Here, we show that the reason for this is that methods targeting foldedness through monitoring amino acid sidechain reactivity also detect changes in conformation and ligand binding, which can be a substantial fraction of the data. We show that the reactivity of only one quarter of cysteine or methionine sidechains in proteins in a urea denaturation curve of mammalian cell lysate can be confidently explained by a two-state unfolding isotherm. Contrary to that expected from unfolding, up to one third of the cysteines decreased reactivity. These cysteines were enriched in proteins with functions relating to unfolded protein stress. One protein, chaperone HSPA8, displayed changes arising from ligand and cofactor binding. Unmasking this hidden information using the approaches outlined here should improve efforts to understand both folding and the remodeling of protein function directly in complex biological settings.

Date: 2022
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DOI: 10.1038/s41467-022-29661-2

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