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.

项目总结-解码同义密码子使用对蛋白质折叠的调节

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