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. 2018 May 3;70(3):488-501.e5.
doi: 10.1016/j.molcel.2018.03.033.

Mapping Degradation Signals and Pathways in a Eukaryotic N-terminome

Ilia Kats  1 , Anton Khmelinskii  1 , Marc Kschonsak  1 , Florian Huber  1 , Robert A Knieß  1 , Anna Bartosik  1 , Michael Knop  2
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Free article

Mapping Degradation Signals and Pathways in a Eukaryotic N-terminome

Ilia Kats et al. Mol Cell. .
Free article

Abstract

Most eukaryotic proteins are N-terminally acetylated. This modification can be recognized as a signal for selective protein degradation (degron) by the N-end rule pathways. However, the prevalence and specificity of such degrons in the proteome are unclear. Here, by systematically examining how protein turnover is affected by N-terminal sequences, we perform a comprehensive survey of degrons in the yeast N-terminome. We find that approximately 26% of nascent protein N termini encode cryptic degrons. These degrons exhibit high hydrophobicity and are frequently recognized by the E3 ubiquitin ligase Doa10, suggesting a role in protein quality control. In contrast, N-terminal acetylation rarely functions as a degron. Surprisingly, we identify two pathways where N-terminal acetylation has the opposite function and blocks protein degradation through the E3 ubiquitin ligase Ubr1. Our analysis highlights the complexity of N-terminal degrons and argues that hydrophobicity, not N-terminal acetylation, is the predominant feature of N-terminal degrons in nascent proteins.

Keywords: N-end rule; N-terminal acetylation; N-terminal methionine excision; N-terminal processing; deep sequencing; massively parallel protein turnover assays; multiplexed protein stability profiling; protein quality control; selective protein degradation.

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