Molecular cell · 2023
Global analysis of aging-related protein structural changes uncovers enzyme-polymerization-based control of longevity.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Paukštytė Jurgita, López Cabezas Rosa María, Feng Yuehan, Tong Kai, Schnyder Daniela, Elomaa Ellinoora, Gregorova Pavlina, Doudin Matteo, Särkkä Meeri, Sarameri Jesse, Lippi Alice, Vihinen Helena, Juutila Juhana, Nieminen Anni, Törönen Petri, Holm Liisa, Jokitalo Eija, Krisko Anita, Huiskonen Juha, Sarin L Peter, Hietakangas Ville, Picotti Paola, Barral Yves, Saarikangas Juha
Аннотация
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.