[Seminar] Polyphosphorylation, a new post-translational modification of proteins

Polyphosphorylation, a new post-translational modification of proteins

Cristina Azevedo

MRC-Laboratory for Molecular Cell Biology,

University College London, London, UK

Abstract

Protein post-translational modifications (PTMs) increase the functional and structural complexity of the proteome allowing for a rapid, controlled and reversible response to environmental cues. There is an ever-increasing number of known PTMs and many others, recalcitrant to the current analytical methods, are likely to exist. Over the past years, I have been working on two non-enzymatic protein post-translational modifications (PTMs), pyro and polyphosphorylation. I characterised how HIV1 virus like particle release is regulated by serine pyrophosphorylation (Azevedo et al., 2009), a PTM occurring after transfer of the beta phosphate from the inositol pyrophosphate (IP7) to a pre-phosphorylated serine. Whilst developing this project, I discovered polyphosphorylation, a PTM in which inorganic polyphosphate (polyP), a linear polymer of orthophosphate residues, is covalently attached to lysine residues within a PASK domain (polyacidic serine and lysine rich region) (Azevedo et al., 2015). Originally, I identified two budding yeast target proteins, Nsr1 (nuclear signal recognition 1) and its interacting partner Top1 (topoisomerase 1). I determined that polyphosphorylation negatively regulates Nsr1/Top1 interaction, localization and Top1 enzymatic function. Recently, I determined that this modification also occurs in higher eukaryotes and in prokaryotes. Screening the Hela and E. coli proteomes with chemically synthetized flag-modified monodisperse short-chain polyP (flag-polyP8-flag) we identified many targets. Gene ontology (GO) analysis between these screens showed that the top most enriched common terms fall under the categories of nucleic acid binding, translation factor activity and ribosomal RNA biogenesis (Azevedo et al., 2018). Interestingly, proteins analysis revealed many common targets between the mammalian and the bacterial proteome demonstrating that polyphosphorylation is likely to be evolutionarily conserved.

Short Bio

Cristina Azevedo has a degree in Agricultural Engineering, from Instituto Superior de Agronomia, Lisbon. She did an “International Masters in Biotechnology” between three universities (UK, Holland and the US). She then moved to the UK where to do a PhD in Plant Pathogen Interactions at John Innes Center in Norwich, where she cloned and characterized Sgt1, a major regulator of plant immunity. After her PhD she moved to London to the Medical Research Council-Laboratory for Molecular Cell Biology as a career development fellow to work on the functional characterization of a new protein post-translational modification. In 2009 she became an investigator Scientist at the same institute.