Structural and genetic variability of the proteostasis network in Saccharomyces cerevisiae.

• Applicant: Dr. Matthias Weith
• Subject Area: General Genetics and Functional Genome Biology ; Structural Biology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440376057

• Final Report Year: 2024

Final Report Abstract

This study explored the cellular network that protects Saccharomyces cerevisiae against the consequences of heat stress treatment by combining detailed structural data on dynamic changes in protein folding with an investigation of the genetic foundation of heat resistance. Leveraging existing multi-omics data on an extensive cross between two yeast strains (S288c-derivate strain BY4716 and vineyard-isolate RM11-1a), we investigated the genetic influence on cellular resistance to heat stress. Our findings highlighted the prominent role of PKA and TOR signaling pathways as major determinants not only of heat resistance but also of the overall state of the cellular molecular network. Furthermore, we employed Limited Proteolysis-Mass Spectrometry (LiP-MS) to study protein structural changes in response to heat stress. This integrated approach allowed the identification of overlaps between the acute cellular response to stress and genetically determined differences in the cellular network state. Notably, we observed structural alterations in key cellular components, such as the plasma membrane proton pump Pma1p, which plays a crucial role in setting cellular pH, following heat treatment. This pump was also regulated by genetic effects on the PKA and TOR-controlled network state, establishing a direct link between structural changes, signaling pathways and cell state regulation. In addition to these detailed mechanistic insights, our study led to the proposition of a new classification of genetic effects based on the network state-regulation model. Furthermore, the broad applicability and predictive power of this model in yeast has motivated us to explore similar network state alterations in human cells in a follow-up project.

Publications

• The impact of genomic variation on protein phosphorylation states and regulatory networks. Molecular Systems Biology, 18(5).
  Grossbach, Jan; Gillet, Ludovic; Clément‐Ziza, Mathieu; Schmalohr, Corinna L.; Schubert, Olga T.; Schütter, Maximilian; Mawer, Julia S. P.; Barnes, Christopher A.; Bludau, Isabell; Weith, Matthias; Tessarz, Peter; Graef, Martin; Aebersold, Ruedi & Beyer, Andreas
  
• Genetic effects on molecular network states explain complex traits. Molecular Systems Biology, 19(8).
  Weith, Matthias; Großbach, Jan; Clement‐Ziza, Mathieu; Gillet, Ludovic; Rodríguez‐López, María; Marguerat, Samuel; Workman, Christopher T.; Picotti, Paola; Bähler, Jürg; Aebersold, Ruedi & Beyer, Andreas
  
• The next step in Mendelian randomization. eLife, 12.
  Weith, Matthias & Beyer, Andreas