Global mapping of protein–metabolite interactions in Saccharomyces cerevisiae reveals that Ser-Leu dipeptide regulates phosphoglycerate kinase activity

Protein–metabolite interactions are of crucial importance for all cellular processes but remain understudied. Here, we applied a biochemical approach named PROMIS, to address the complexity of the protein–small molecule interactome in the model yeast Saccharomyces cerevisiae . By doing so, we provid...

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Published in:	Communications biology Vol. 4; no. 1; p. 181
Main Authors:	Luzarowski, Marcin, Vicente, Rubén, Kiselev, Andrei, Wagner, Mateusz, Schlossarek, Dennis, Erban, Alexander, de Souza, Leonardo Perez, Childs, Dorothee, Wojciechowska, Izabela, Luzarowska, Urszula, Górka, Michał, Sokołowska, Ewelina M., Kosmacz, Monika, Moreno, Juan C., Brzezińska, Aleksandra, Vegesna, Bhavana, Kopka, Joachim, Fernie, Alisdair R., Willmitzer, Lothar, Ewald, Jennifer C., Skirycz, Aleksandra
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 10-02-2021 Nature Publishing Group Nature Portfolio
Subjects:	631/1647/296 631/45/320 631/45/607 631/45/612 82/16 82/58 82/83 Biology Biomedical and Life Sciences Chaperones Energy Metabolism Glycolysis Kinases Life Sciences Metabolism Metabolites Metabolome Metabolomics Peptide mapping Phosphoglycerate kinase Phosphoglycerate Kinase - genetics Phosphoglycerate Kinase - metabolism Proteasomes Protein Interaction Maps Protein turnover Proteins Proteolysis Proteome Proteomics Saccharomyces cerevisiae Saccharomyces cerevisiae - enzymology Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Supplements Vegetal Biology Yeast Proteins Enzymes Metabolomics Mass spectrometry
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Summary:	Protein–metabolite interactions are of crucial importance for all cellular processes but remain understudied. Here, we applied a biochemical approach named PROMIS, to address the complexity of the protein–small molecule interactome in the model yeast Saccharomyces cerevisiae . By doing so, we provide a unique dataset, which can be queried for interactions between 74 small molecules and 3982 proteins using a user-friendly interface available at https://promis.mpimp-golm.mpg.de/yeastpmi/ . By interpolating PROMIS with the list of predicted protein–metabolite interactions, we provided experimental validation for 225 binding events. Remarkably, of the 74 small molecules co-eluting with proteins, 36 were proteogenic dipeptides. Targeted analysis of a representative dipeptide, Ser-Leu, revealed numerous protein interactors comprising chaperones, proteasomal subunits, and metabolic enzymes. We could further demonstrate that Ser-Leu binding increases activity of a glycolytic enzyme phosphoglycerate kinase ( Pgk1 ). Consistent with the binding analysis, Ser-Leu supplementation leads to the acute metabolic changes and delays timing of a diauxic shift. Supported by the dipeptide accumulation analysis our work attests to the role of Ser-Leu as a metabolic regulator at the interface of protein degradation and central metabolism. Marcin Luzarowski et al. use a new method PROMIS for systematic analysis of protein small molecule interactions in yeast. Their work provides an experimentally-derived catalogue of protein–metabolite complexes in S. cerevisiae and reveals that the Ser-Leu dipeptide activates Pgk1, and alters cellular metabolism.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC7876005
ISSN:	2399-3642 2399-3642
DOI:	10.1038/s42003-021-01684-3