Global analysis of aging-related protein structural changes uncovers enzyme-polymerization-based control of longevity.

Aging is associated with progressive phenotypic changes. Virtually all cellular phenotypes are produced by proteins, and their structural alterations can lead to age-related diseases. However, we still lack comprehensive knowledge of proteins undergoing structural-functional changes during cellular aging and their contributions to age-related phenotypes. Here, we conducted proteome-wide analysis of early age-related protein structural changes in budding yeast using limited proteolysis-mass spectrometry (LiP-MS). The results, compiled in online ProtAge catalog, unraveled age-related functional changes in regulators of translation, protein folding, and amino acid metabolism. Mechanistically, we found that folded glutamate synthase Glt1 polymerizes into supramolecular self-assemblies during aging, causing breakdown of cellular amino acid homeostasis. Inhibiting Glt1 polymerization by mutating the polymerization interface restored amino acid levels in aged cells, attenuated mitochondrial dysfunction, and led to lifespan extension. Altogether, this comprehensive map of protein structural changes enables identifying mechanisms of age-related phenotypes and offers opportunities for their reversal.

Winter is coming: Regulation of cellular metabolism by enzyme polymerization in dormancy and disease.

Metabolism feeds growth. Accordingly, metabolism is regulated by nutrient-sensing pathways that converge growth promoting signals into biosynthesis by regulating the activity of metabolic enzymes. When the environment does not support growth, organisms invest in survival. For cells, this entails transitioning into a dormant, quiescent state (G0). In dormancy, the activity of biosynthetic pathways is dampened, and catabolic metabolism and stress tolerance pathways are activated. Recent work in yeast has demonstrated that dormancy is associated with alterations in the physicochemical properties of the cytoplasm, including changes in pH, viscosity and macromolecular crowding. Accompanying these changes, numerous metabolic enzymes transition from soluble to polymerized assemblies. These large-scale self-assemblies are dynamic and depolymerize when cells resume growth. Here we review how enzyme polymerization enables metabolic plasticity by tuning carbohydrate, nucleic acid, amino acid and lipid metabolic pathways, with particular focus on its potential adaptive value in cellular dormancy.