Enzyme-assisted post-translational modifications (PTMs) constitute a major means of signaling across different cellular compartments. However, how non-enzymatic PTMs such as electrophilic protein modifications—despite their direct relevance to covalent drug development—impinge on cross-compartment, or more broadly, locale-specific signal transduction remains inaccessible as current target-ID technologies offer limited spatiotemporal resolution, and proximity mapping tools are also not guided by specific, biologically-relevant, ligand chemotypes. I will discuss how reimagining precision localised electrophile delivery concept has enabled us to establish a quantitative and direct profiling platform applicable <i>in vivo </i>(<i>Localis-rex</i>), that ranks responsivity of inter-organelle- or tissue-specific sub-proteomes to non-enzymatic PTMs, and how application of this method has unveiled that even small fractions of endogenous proteins existing outside their canonical locale can show significantly-elevated electrophilic-metabolite sensing against the protein in its canonical locale. This minority of electrophile-sensing proteins can strongly influence activity of the bulk protein and hence cell decision making in cells and animals.

Lighting the way: Function-guided proximity mapping and precision signaling interrogations open up new opportunities

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.