Threonine-rich carboxyl-terminal extension drives aggregation of stalled polypeptides

IF 14.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Weili Denyse Chang, Mi-Jeong Yoon, Kian Hua Yeo, Young-Jun Choe
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引用次数: 0

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.

Abstract Image

富含苏氨酸的羧基末端延伸推动了停滞多肽的聚集
翻译受损 mRNA 的核糖体可能会停滞,并过早地分裂成大亚基和小亚基。分裂后的大核糖体亚基可以继续延长停滞的多肽。在酵母中,这种不依赖于 mRNA 的翻译会将 C 端丙氨酸/苏氨酸尾(CAT 尾)附加到停滞的多肽上。如果不被核糖体相关质量控制(RQC)降解,CAT 尾的滞留多肽就会形成聚集体。CAT 尾部是一个由丙氨酸和苏氨酸组成的低复杂性区域,它是如何驱动蛋白质聚集的仍是未知数。在这项研究中,我们证明了 C 端富含多苏氨酸或苏氨酸的尾部会形成抗清洁剂的聚集体。这些聚集体对苏氨酸含量较低的较短尾部表现出强大的播种效应,从而阐明了异质 CAT 尾部是如何共同聚集的。多苏氨酸聚集体会封闭分子伴侣,扰乱蛋白稳态并引发热休克反应。此外,聚苏氨酸还能交叉融合抗清洁剂的聚丝氨酸聚集体,这表明这两种聚集体在结构上具有相似性。这项研究确定了聚苏氨酸和聚丝氨酸是一组不同的易聚集蛋白质基团。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Cell
Molecular Cell 生物-生化与分子生物学
CiteScore
26.00
自引率
3.80%
发文量
389
审稿时长
1 months
期刊介绍: Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.
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