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Cotranslational control of functional and pathological conformational switching of nascent polypeptides

新生多肽功能和病理构象转换的共翻译控制

基本信息

批准号：
10728945
负责人：
Dale Cameron
金额：
$ 41.85万
依托单位：
URSINUS COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10728945
关键词：
Amino Acid Sequence Area Biological Process Cell physiology Cells Collaborations Complex Cues Data Development Disease Ensure Environment Equilibrium Event Exposure to Failure Foundations Funding Gene Expression Genotype Goals Grant Human Intervention Kinetics Knowledge Link Literature Mission Modeling Molecular Chaperones Molecular Conformation N-terminal National Institute of General Medical Sciences Onset of illness Outcome Pathogenicity Pathologic Phenotype Physiological Positioning Attribute Prevention strategy Prions Process Proteins Proteome Public Health Publishing Quality Control RNA Processing Research Ribosomes Role Science Stress Testing Therapeutic Intervention Time Translations United States National Institutes of Health Work amyloid formation amyloidogenesis career graduate school human disease infancy innovation pharmacologic polypeptide prevent prion-like protein folding protein misfolding proteostasis proteotoxicity response targeted treatment three dimensional structure undergraduate student virtual yeast prion

项目摘要

Project Summary/Abstract Many proteins have been identified to possess prion-like domains (PrLDs) capable of conformational switching between alternative three-dimensional structures. Conformational switching can be functional or pathological and the earliest point at which it could be regulated is during synthesis of the PrLD, especially for N-terminal PrLDs that emerge first from the ribosomal exit tunnel. However, the extent to which switching is regulated cotranslationally is largely unexplored, and our understanding of the physiological consequences of switching is in its infancy. Thus, elucidating ribosome-associated mechanisms and physiological impacts of conformational switching represents a critical barrier to advancing our understanding of how cells navigate the delicate balance between achieving proteostasis versus pathological protein misfolding. The applicant’s long-term goal is to decipher the mechanisms by which cells sense and respond to stress to maintain proteostasis, with a goal of better understanding the physiological significance of conformational switching in these processes. The overall objective of this application is to determine the contributions of cotranslational events in functional and pathological conformational switching of nascent chains, and the impact on gene expression of switching of a prion-forming protein. The central hypothesis is that conformational switching of nascent chains is governed by the interplay of translation kinetics and ribosome-associated factors in response to environmental cues and can result in both beneficial and pathogenic phenotypes. This hypothesis is based on the applicant’s published work and preliminary data, as well as published work from others. The rationale for the proposed research is that elucidating the contributions of ribosome-associated processes in conformational switching of nascent chains will revolutionize our understanding of proteostasis and pave the way for pharmacological manipulation to curtail pathogenic misfolding events. Using yeast prion-forming proteins and a human disease-associated protein sequence as models, this hypothesis will be tested by pursuing three specific aims: 1) Identify the roles of ribosome pausing and proteotoxic stress in modulating conformational switching of nascent chains; 2) Identify the roles of RAC and NAC in modulating conformational switching of nascent chains; and 3) Define physiological consequences of conformational switching of a prion-forming protein. The proposed work is innovative because it represents a substantial departure from the status quo by examining the earliest possible time-point in amyloidogenesis and by assessing the physiological consequences of functional conformational switching. The contribution of this work is expected to be detailed understanding of ribosome-associated mechanisms regulating cotranslational amyloid formation and the resulting physiological consequences. This contribution will be significant because cotranslational amyloid formation constitutes the earliest misfolding event against which pharmacological intervention could be targeted; thus, an understanding of the regulatory mechanisms governing the balance between functional and pathogenic conformational switching is urgently needed to advance the field.

项目总结/文摘

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Investigating the Roles of NAC and RAC in Suppressing Prion Formation in Saccharomyces cerevisiae.

研究 NAC 和 RAC 在抑制酿酒酵母朊病毒形成中的作用。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Kitterman,Erica;Kim,Seongchan;Yilanjian,Mark;Kelly,Christina;Cameron,Dale
通讯作者：
Cameron,Dale

Prion-dependent proteome remodeling in response to environmental stress is modulated by prion variant and genetic background.

响应环境压力的朊病毒依赖性蛋白质组重塑受到朊病毒变异和遗传背景的调节。

DOI：
10.1080/19336896.2019.1583041
发表时间：
2019
期刊：
Prion
影响因子：
2.3
作者：
Allwein,Ben;Kelly,Christina;Kammoonah,Shaima;Mayor,Thibault;Cameron,DaleM
通讯作者：
Cameron,DaleM

A Novel Connection Between [PSI+ ] Prion Formation and RNA Splicing in Saccharomyces cerevisiae.

酿酒酵母中 [PSI] 朊病毒形成与 RNA 剪接之间的新联系。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Jones,ElizabethA;Riccitelli,AudreyN;Cameron,DaleM;Kress,TracyL
通讯作者：
Kress,TracyL

The human ribosome-associated complex suppresses prion formation in yeast.

DOI：
10.1002/prot.26461
发表时间：
2023-06
期刊：
Proteins
影响因子：
2.9
作者：
通讯作者：

A Yeast Model System to Study the Human Orthologs of the Ribosome-Associated Complex.

用于研究核糖体相关复合物的人类直系同源物的酵母模型系统。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Marley,Amanda;Kim,Seongchan;FandinoPachon,Nikole;Zeibekis,Theodora;Kitterman,Erica;Kelly,Christina;Cameron,DaleM
通讯作者：
Cameron,DaleM