Conserved homologues of the Hrd1 ubiquitin ligase target for degradation proteins that persistently or aberrantly engage the endoplasmic reticulum translocon, including mammalian apolipoprotein B (apoB; the major protein component of low-density lipoproteins) and the artificial yeast protein Deg1-Sec62. A complete understanding of the molecular mechanism by which translocon-associated proteins are recognized and degraded may inform the development of therapeutic strategies for

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... d pathologies. Both apoB and Deg1-Sec62 are extensively post-translationally modified. Mass spectrometry of a variant of Deg1-Sec62 revealed that the protein is acetylated at the N-terminal methionine and two internal lysine residues. N-terminal and internal acetylation regulates the degradation of a variety of unstable proteins. However, preventing N-terminal and internal acetylation had no detectable consequence for Hrd1mediated proteolysis of Deg1-Sec62. Our data highlight the importance of empirically validating the role of post-translational modifications and sequence motifs on protein degradation, even when such elements have previously been demonstrated sufficient to destine other proteins for destruction. PeerJ reviewing PDF | (Manuscript to be reviewed 1 Acetylation of N-terminus and two internal amino acids is dispensable for degradation of a 2 protein that aberrantly engages the endoplasmic reticulum translocon 3 4 Manuscript to be reviewed 23 ABSTRACT 24 25 Conserved homologues of the Hrd1 ubiquitin ligase target for degradation proteins that 26 persistently or aberrantly engage the endoplasmic reticulum translocon, including mammalian 27 apolipoprotein B (apoB; the major protein component of low-density lipoproteins) and the 28 artificial yeast protein Deg1-Sec62. A complete understanding of the molecular mechanism by 29 which translocon-associated proteins are recognized and degraded may inform the development 30 of therapeutic strategies for cholesterol-related pathologies. Both apoB and Deg1-Sec62 are 31 extensively post-translationally modified. Mass spectrometry of a variant of Deg1-Sec62 32 revealed that the protein is acetylated at the N-terminal methionine and two internal lysine 33 residues. N-terminal and internal acetylation regulates the degradation of a variety of unstable 34 proteins. However, preventing N-terminal and internal acetylation had no detectable 35 consequence for Hrd1-mediated proteolysis of Deg1-Sec62. Our data highlight the importance of 36 empirically validating the role of post-translational modifications and sequence motifs on protein 37 degradation, even when such elements have previously been demonstrated sufficient to destine 38 other proteins for destruction. PeerJ reviewing PDF | (