Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding.
Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding.
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DOI：
10.1038/ncomms5383
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发表时间：
2014-07-15
影响因子：
16.6
通讯作者：
Serio, Tricia R.
中科院分区：
文献类型：
--
作者：
Holmes, William M.;Mannakee, Brian K.;Gutenkunst, Ryan N.;Serio, Tricia R.
n端乙酰化是真核生物中最普遍的蛋白质修饰之一。虽然n端乙酰化的丧失与许多异常有关，但这些影响的分子基础仅在少数情况下已知，其中单一因素的乙酰化与结合亲和性或代谢稳定性有关。相比之下，n端乙酰化对大多数蛋白质组的影响及其对表型的组合贡献尚不清楚。在这里，通过研究酵母朊病毒[PSI+]， Sup35蛋白的淀粉样蛋白，我们发现n端乙酰化的缺失促进了一般蛋白质的错误折叠，伴侣蛋白重新部署到这些底物上，以及相应的应激反应。这些蛋白停滞的变化，加上未乙酰化的Sup35淀粉样蛋白稳定性的下降，减少了朊病毒聚集体的大小，并逆转了它们的表型后果。因此，n端乙酰化的丧失及其在蛋白质生物发生中先前未预料到的作用，在全球范围内导致蛋白质组产生独特的表型。
N-terminal acetylation is among the most ubiquitous of protein modifications in eukaryotes. While 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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影响因子：
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