Post-translational modifications of protein backbones
The polypeptide backbone makes up approximately 50% of every protein's mass. Originally thought to be inert, emerging evidence suggests that protein backbones are subject to a plethora of site-specific post-translational modifications. Similarly to well-studied modifications of amino acid side chains, backbone modifications can control protein structure and function. We are developing and applying a suite of chemical biology technologies to reveal when, where and how backbone modifications impact biological processes.
Proteins are subject to spontaneous modifications, contributing to senescence phenotypes across all kingdoms of life. For example, asparagine and aspartate residues can rearrange to isoaspartate, and long-lived proteins including eye lens crystalline contain significant amounts of isoaspartate. We aim to elucidate the biochemical, biophysical and cellular mechanisms of isoaspartate formation and explore the exciting possibility that this post-translational modification is harnessed as a molecular timer in biology.
Iso-aspartate formation as a molecular timer.
Post-translational modifications of the polypeptide backbone.
We employ cutting edge protein semi-synthesis methods to prepare site-specifically modified proteins: chemical peptide synthesis enables the incorporation of diverse modifications and native chemical ligation (a chemo-selective ligation strategy) permits the precise attachment of synthetic fragments to large recombinant proteins. Full-length proteins generated in this way enable us to directly measure how post-translational modifications control functional properties in biochemical, biophysical and cellular assays.
Protein semi-synthesis via native chemical ligation.