Decoding the regulation of protein folding by synonymous codon usage

通过同义密码子使用解码蛋白质折叠的调控

• 批准号: 10673883
• 负责人: Patricia Louise Clark
• 金额: $ 109.55万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673883
• 关键词: Adverse effects; Amino Acid Sequence; Award; Buffers; Cells; Codon Nucleotides; Complex; Disease; Genetic; Genetic Diseases; Genome; Genomics; Goals; Human Genetics; Lead; Link; Measures; Molecular Chaperones; Mutation; Pattern; Peptide Hydrolases; Phenotype; Predisposition; Production; Proteins; Proteome; Regulation; Structure; Time; cell growth; design; fitness; in vivo; next generation; novel; novel strategies; preservation; protein folding; protein function; proteostasis

PROJECT SUMMARY - Decoding the regulation of protein folding by synonymous codon usage Synonymous mutations are widespread in complex, polygenic diseases but are typically regarded as phenotypically silent, as they preserve the amino acid sequence of the encoded protein. Yet, synonymous mutations can significantly perturb protein homeostasis through a variety of mechanisms, including perturbing the folding mechanism of the encoded protein. Recently, my lab discovered that synonymous codon-induced changes to protein folding can be large enough to (a) exceed the protein homeostatic buffering provided by molecular chaperones and (b) lead to a dramatic two-fold decrease in cell growth rate. For these proteins, changing the codon usage pattern produces a folded protein with an altered structure, which leads to changes in activity and/or susceptibility to degradation by cellular proteases. The profound implication of these results is that codon usage represents another level of information encoded within genomes, linking together “silent” genetic differences with proper protein function and regulation of a potentially broad range of cellular mechanisms. Historically, however, studying perturbations to protein folding mechanisms in vivo has presented immense technical challenges. For this reason, to date only a few examples have been identified of connections between codon usage and protein folding. As a result, we lack a comprehensive picture of the extent to which synonymous codon usage contributes to the production of a functional proteome and how synonymous mutations perturb protein homeostasis. This Pioneer Award project is designed to break through existing technical challenges, developing a novel approach to (i) broadly measure for the first time the number and types of proteins with folding mechanisms sensitive to synonymous codon usage, across an entire proteome and (ii) deeply interrogate which codon usage patterns and features best support proper protein folding in vivo. The ambitious, overarching goal of this project is to enable a next generation of genomic inference by developing a predictive understanding of the synonymous codon usage patterns that best support production of a functional proteome and the dysregulation that leads to human genetic disease.

项目摘要 - 通过合成密码子使用解码蛋白质折叠的调节 同义突变在复杂的多基因疾病中广泛存在，但通常被认为是 平静地静音，因为它们保留了编码蛋白的氨基酸序列。但是，同义词 突变可以通过多种机制显着扰动蛋白质稳态，包括干扰 编码蛋白的折叠机制。最近，我的实验室发现合成密码子引起的 蛋白质折叠的变化可能足够大，以至于（a）超过蛋白质的稳态缓冲 分子伴侣和（b）导致细胞生长速率的急剧下降。对于这些蛋白质， 更改密码子的使用模式会产生带有改变结构的折叠蛋白，从而导致变化 在活性和/或通过细胞蛋白酶降解的敏感性。这些结果的深刻含义是 该密码子的使用代表了基因组中编码的另一个信息，将“沉默”链接在一起 具有适当蛋白质功能的遗传差异和可能广泛的细胞的调节 机制。然而，从历史上看，研究对蛋白质折叠机制的扰动已经提出 巨大的技术挑战。因此，迄今为止仅确定了几个示例 在密码子使用和蛋白质折叠之间。结果，我们缺乏全面的了解程度 同义密码子的用法有助于产生功能蛋白质组以及如何同义 突变扰动蛋白稳态。该开拓者奖项目旨在突破现有 技术挑战，开发了一种新颖的方法，以（i）首次大致测量数量和类型 具有对同义密码子使用敏感的折叠机制的蛋白质，整个蛋白质组和（ii） 深入询问哪种密码子使用模式并具有最佳的体内蛋白质折叠。这 该项目的雄心勃勃的总体目标是通过开发一个来实现下一代基因组推断 对同义密码子使用模式的预测理解，这些模式最能支持功能的生产 蛋白质组和导致人类遗传疾病的失调。

项目成果

CHARMING: Harmonizing synonymous codon usage to replicate a desired codon usage pattern.

迷人：协调同义密码子使用以复制所需的密码子使用模式。

• DOI: 10.1002/pro.4223
• 发表时间: 2022
• 期刊: Protein science : a publication of the Protein Society
• 作者: Wright,Gabriel;Rodriguez,Anabel;Li,Jun;Milenkovic,Tijana;Emrich,ScottJ;Clark,PatriciaL
• 通讯作者: Clark,PatriciaL