RT Journal Article
SR Electronic
T1 Global analysis of aging-related protein structural changes uncovers enzyme polymerization-based control of longevity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.23.524173
DO 10.1101/2023.01.23.524173
A1 Jurgita Paukštytė
A1 Rosa María López Cabezas
A1 Yuehan Feng
A1 Kai Tong
A1 Daniela Schnyder
A1 Ellinoora Elomaa
A1 Pavlina Gregorova
A1 Matteo Doudin
A1 Meeri Särkkä
A1 Jesse Sarameri
A1 Alice Lippi
A1 Helena Vihinen
A1 Juhana Juutila
A1 Anni Nieminen
A1 Petri Törönen
A1 Liisa Holm
A1 Eija Jokitalo
A1 Anita Krisko
A1 Juha Huiskonen
A1 L. Peter Sarin
A1 Ville Hietakangas
A1 Paola Picotti
A1 Yves Barral
A1 Juha Saarikangas
YR 2023
UL http://biorxiv.org/content/early/2023/01/23/2023.01.23.524173.abstract
AB Aging is associated with progressive phenotypic changes over time. Virtually all cellular phenotypes are produced by proteins and structural alterations in proteins can lead to age-related diseases. Nonetheless, comprehensive knowledge of proteins undergoing structural-functional changes during cellular aging and their contribution to age-related phenotypes is lacking. Here, we conducted proteome-wide analysis of early age-related protein structural changes in budding yeast using limited proteolysis-mass spectrometry. The results, compiled in online ProtAge-catalog, unravelled 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 life span extension. Altogether, this comprehensive map of protein structural changes enables identifying novel mechanisms of age-related phenotypes and offers opportunities for their reversal.Competing Interest StatementP.P. is a scientific advisor for the company Biognosys AG (Zurich, Switzerland) and PP and YF are inventors of a patent licensed by Biognosys AG that covers the LiP-MS method used in this manuscript.