Changes of Cell Biochemical States Are Revealed in Protein Homomeric Complex Dynamics

• Published in: Cell Vol. 175; no. 5; pp. 1418 - 1429.e9
• Main Authors: Stynen, Bram, Abd-Rabbo, Diala, Kowarzyk, Jacqueline, Miller-Fleming, Leonor, Aulakh, Simran Kaur, Garneau, Philippe, Ralser, Markus, Michnick, Stephen W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.11.2018; Cell Press
• Subjects: aging; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Genetic Complementation Test; Humans; Iron - metabolism; iron homeostasis; large-scale screen; Metalloproteins - genetics; Metalloproteins - metabolism; metformin; Metformin - pharmacology; protein-protein interactions; rapamycin; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Sirolimus - pharmacology; metformin; aging; iron homeostasis; large-scale screen; protein-protein interactions; rapamycin
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.09.050

We report here a simple and global strategy to map out gene functions and target pathways of drugs, toxins, or other small molecules based on “homomer dynamics” protein-fragment complementation assays (hdPCA). hdPCA measures changes in self-association (homomerization) of over 3,500 yeast proteins in yeast grown under different conditions. hdPCA complements genetic interaction measurements while eliminating the confounding effects of gene ablation. We demonstrate that hdPCA accurately predicts the effects of two longevity and health span-affecting drugs, the immunosuppressant rapamycin and the type 2 diabetes drug metformin, on cellular pathways. We also discovered an unsuspected global cellular response to metformin that resembles iron deficiency and includes a change in protein-bound iron levels. This discovery opens a new avenue to investigate molecular mechanisms for the prevention or treatment of diabetes, cancers, and other chronic diseases of aging. [Display omitted] •hdPCA reveals dynamics of protein homeostasis•hdPCA uncovers the responses of most biochemical pathways to cell perturbations•An hdPCA screen reveals that metformin induces an iron deficiency-like state•hdPCA can be applied to mapping out biochemical pathways and networks Assessment of the global effects of small molecules on protein self-association in yeast provides insights into target pathways and mechanisms of action.