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Folding and Chaperone Interactions of Multi-domain Proteins

多结构域蛋白质的折叠和分子伴侣相互作用

基本信息

批准号：
10662086
负责人：
Christian Kaiser
金额：
$ 20.6万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662086
关键词：
Aging Alzheimer&apos s Disease Bacteria Binding Biological Biology Biophysics Brain Cell physiology Cells Codon Nucleotides Communication Complement Complex Contracts Coupled Cultured Cells Cytosol Detection Disease Ensure Eukaryota Event Future Geometry Goals In Vitro Individual Length Link Malignant Neoplasms Measurement Measures Mechanics Methods Molecular Molecular Chaperones Muscle Neurodegenerative Disorders Neurons Nutrient Outcome Parkinson Disease Pathway interactions Peptides Peptidyltransferase Process Property Protein Biosynthesis Proteins Proteome Regulation Resolution Ribosomes Role Shapes Structure Tertiary Protein Structure Translations Variant Work Yeasts attenuation cytotoxic defined contribution experimental study in vivo insight laser tweezer mechanical force novel therapeutic intervention overexpression polypeptide protein aggregation protein folding protein misfolding proteostasis reconstitution ribosome profiling single molecule three dimensional structure

项目摘要

Project Summary Combining several functional units, termed domains, into a single polypeptide chain is a common evolutionary strategy for creating biological complexity. The resulting multi-domain proteins are prevalent in all proteomes and carry out essential cellular functions. However, the increased functional complexity of these large proteins complicates their folding into native functional structures. In contrast to many smaller proteins or individual domains, multi-domain proteins are prone to misfolding and potentially cytotoxic aggregation. In the cell, several factors ensure efficient folding. Folding begins co- translationally, while the ribosome still synthesizes the polypeptide. Molecular chaperones begin to interact with the nascent multi-domain protein as soon as it emerges from the ribosome. Co- translational folding and chaperone interactions are recognized as crucial for efficient multi-domain protein folding. However, these processes remain poorly defined at the molecular level, because it is technically challenging to study them. The goal of this project is to define principles of co-translational folding and chaperone function to better understand how complex multi-domain proteins robustly reach their functional structures. We are using a combination of single-molecule biophysics and live-cell experiments to accomplish this goal. With optical tweezers, we are studying the folding pathways of nascent multi-domain proteins at the single-molecule level. Manipulation of individual molecules is ideally suited to resolve complex folding pathways of nascent proteins, elucidate the contributions of the ribosome and molecular chaperones to the folding process, and determine how co-translational folding and protein synthesis are coupled and regulated to ensure robust outcomes. These detailed in vitro studies are complemented by experiments in live cells that detect co-translational folding events in multi-domain proteins. Protein misfolding and aggregation, misregulation of protein synthesis and decline of chaperone function are hallmarks of many aging-related diseases. Our studies may ultimately provide a mechanistic basis for discovering novel therapeutic strategies to treat some of these diseases.

项目总结