Monday, February 28, 2022

Global profiling of phosphorylation-dependent changes in cysteine reactivity [@estherkemper1

Kemper, E.K., Zhang, Y., Dix, M.M. & Benjamin F. Cravatt.

Nat Methods, 2022

Proteomics has revealed that the ~20,000 human genes engender a far greater number of proteins, or proteoforms, that are diversified in large part by post-translational modifications (PTMs). How such PTMs affect protein structure and function is an  active  area  of  research  but  remains  technically  challenging  to  assess  on  a  proteome-wide  scale.  Here,  we  describe  a  chemical proteomic method to quantitatively relate serine/threonine phosphorylation to changes in the reactivity of cysteine residues, a parameter that can affect the potential for cysteines to be post-translationally modified or engaged by covalent drugs. Leveraging the extensive high-stoichiometry phosphorylation occurring in mitotic cells, we discover numerous cysteines that exhibit phosphorylation-dependent changes in reactivity on diverse proteins enriched in cell cycle regulatory pathways. The discovery  of  bidirectional  changes  in  cysteine  reactivity often  occurring  in  proximity  to  serine/threonine  phosphorylation events points to the broad impact of phosphorylation on the chemical reactivity of proteins and the future potential to create small-molecule probes that differentially target proteoforms with PTMs.

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