The Pivotal Role of Protein Phosphorylation in the Control of Yeast Central Metabolism

Abstract

Protein phosphorylation is the most frequent eukaryotic post-translational modification and can act as either a molecular switch or rheostat for protein functions. The deliberate manipulation of protein phosphorylation has great potential for regulating specific protein functions with surgical precision, rather than the gross effects gained by the over/underexpression or complete deletion of a protein-encoding gene. In order to assess the impact of phosphorylation on central metabolism, and thus its potential for biotechnological and medical exploitation, a compendium of highly confident protein phosphorylation sites (p-sites) for the model organism Saccharomyces cerevisiae has been analyzed together with two more datasets from the fungal pathogen Candida albicans. Our analysis highlights the global properties of the regulation of yeast central metabolism by protein phosphorylation, where almost half of the enzymes involved are subject to this sort of post-translational modification. These phosphorylated enzymes, compared to the nonphosphorylated ones, are more abundant, regulate more reactions, have more protein–protein interactions, and a higher fraction of them are ubiquitinated. The p-sites of metabolic enzymes are also more conserved than the background p-sites, and hundreds of them have the potential for regulating metabolite production. All this integrated information has allowed us to prioritize thousands of p-sites in terms of their potential phenotypic impact. This multi-source compendium should enable the design of future high-throughput (HTP) mutation studies to identify key molecular switches/rheostats for the manipulation of not only the metabolism of yeast, but also that of many other biotechnologically and medically important fungi and eukaryotes.

Three J-proteins impact Hsp104-mediated variant-specific prion elimination: a new critical role for a low-complexity domain

“…Experimentally, Sis1's G/F region, Ydj1's G/F region, and Apj1's QS region have already been found to completely lack phosphorylation and ubiquitination (Swaney et al 2013). However, phosphorylation of serine residues can change dramatically in response to cell stress (Vlastaridis et al 2017). It is plausible that phosphorylation was not detected in these three J-proteins' IDRs simply because cells were grown under ideal conditions, and that phosphorylation may only be present under stressful conditions and/or when cells harbor [PSI + ], a hypothesis that remains to be investigated.…”

Proteome allocations change linearly with specific growth rate of Saccharomyces cerevisiae under glucose-limitation

“…Phosphorylation of proteins is a reversible post-translational modi cation of amino acid residues (serine, threonine, or tyrosine) by introducing a covalently bound phosphate group to the protein molecule, and it alters the structural conformation of the protein, causing it to become activated, deactivated, or having a modi ed function 30 . In yeast, more than half of the ~900 metabolic enzymes have phosphorylation sites 31,32 .…”

Progressive Phosphorylation Modulates the Self-Association of a Variably Modified Histone H3 Peptide

“…However, it appears that phosphorylation thresholds are of critical importance (Borg et al, 2007). More recently, it was suggested and experimentally documented that multisite phosphorylation also operates as a "rheostat" (Pufall et al, 2005;Garske et al, 2010;Bah et al, 2015;Humphrey et al, 2015;Andrews et al, 2016b;Vlastaridis et al, 2017). According to this model, several phosphorylation sites in a protein region, irrespective of their precise position, collectively contribute to the modification of proteins and form clusters, which operate as the actual functional units.…”