1. Threonine-rich carboxyl-terminal extension drives aggregation of stalled polypeptides.
- Author
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Chang WD, Yoon MJ, Yeo KH, and Choe YJ
- Subjects
- Protein Biosynthesis, Alanine metabolism, Alanine chemistry, Alanine genetics, Proteostasis, Heat-Shock Response, Molecular Chaperones metabolism, Molecular Chaperones genetics, Molecular Chaperones chemistry, RNA-Binding Proteins, Threonine metabolism, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins metabolism, Saccharomyces cerevisiae Proteins genetics, Saccharomyces cerevisiae Proteins chemistry, Protein Aggregates, Ribosomes metabolism, Ribosomes genetics, Peptides metabolism, Peptides chemistry, Peptides genetics
- Abstract
Ribosomes translating damaged mRNAs may stall and prematurely split into their large and small subunits. The split large ribosome subunits can continue elongating stalled polypeptides. In yeast, this mRNA-independent translation appends the C-terminal alanine/threonine tail (CAT tail) to stalled polypeptides. If not degraded by the ribosome-associated quality control (RQC), CAT-tailed stalled polypeptides form aggregates. How the CAT tail, a low-complexity region composed of alanine and threonine, drives protein aggregation remains unknown. In this study, we demonstrate that C-terminal polythreonine or threonine-enriched tails form detergent-resistant aggregates. These aggregates exhibit a robust seeding effect on shorter tails with lower threonine content, elucidating how heterogeneous CAT tails co-aggregate. Polythreonine aggregates sequester molecular chaperones, disturbing proteostasis and provoking the heat shock response. Furthermore, polythreonine cross-seeds detergent-resistant polyserine aggregation, indicating structural similarity between the two aggregates. This study identifies polythreonine and polyserine as a distinct group of aggregation-prone protein motifs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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