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Nat Commun. 2014 Jul 15;5:4383. doi: 10.1038/ncomms5383.

Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding.

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1] Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, Rhode Island 02912, USA [2].
Graduate Interdisciplinary Program in Statistics, University of Arizona, 1548 East Drachman Street, Tucson, Arizona 85721, USA.
Department of Molecular and Cellular Biology, University of Arizona, 1007 East Lowell Street, Tucson, Arizona 85721, USA.


Amino-terminal acetylation is among the most ubiquitous of protein modifications in eukaryotes. Although loss of N-terminal acetylation is associated with many abnormalities, the molecular basis of these effects is known for only a few cases, where acetylation of single factors has been linked to binding avidity or metabolic stability. In contrast, the impact of N-terminal acetylation for the majority of the proteome, and its combinatorial contributions to phenotypes, are unknown. Here, by studying the yeast prion [PSI(+)], an amyloid of the Sup35 protein, we show that loss of N-terminal acetylation promotes general protein misfolding, a redeployment of chaperones to these substrates, and a corresponding stress response. These proteostasis changes, combined with the decreased stability of unacetylated Sup35 amyloid, reduce the size of prion aggregates and reverse their phenotypic consequences. Thus, loss of N-terminal acetylation, and its previously unanticipated role in protein biogenesis, globally resculpts the proteome to create a unique phenotype.

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