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Cullin mediated protein turnover in skeletal and cardiac muscles

Cullin 介导骨骼肌和心肌中的蛋白质周转

基本信息

批准号：
8830992
负责人：
Stephan Lange
金额：
$ 24.53万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8830992
关键词：
Actinin Animal Model Attention Autophagocytosis Binding Biochemical Biological Biological Process Calcium Calpain Cardiac Cardiomyopathies Caspase Cell Survival Cullin Proteins Data Development Dilated Cardiomyopathy Disease Enzymes Exhibits Family Goals Half-Life Homologous Gene In Vitro Inclusion Bodies Investigation Knock-out Knockout Mice Ligase Limb-Girdle Muscular Dystrophies Link Literature Maintenance Mediating Methods Microfilaments Modeling Molecular Muscle Muscle Development Muscle Fibers Muscle Proteins Muscle function Myocardium Myofibrils Myopathy Nature Peptide Hydrolases Physiological Physiology Play Property Protein Family Proteins Reporting Research Research Project Grants Research Proposals Role Sarcomeres Sarcoplasmic Reticulum Signal Pathway Signal Transduction Skeletal Muscle Striated Muscles Structure System Ubiquitin abstracting connectin cullin-3 genetic linkage analysis in vivo insight interest macromolecular assembly multicatalytic endopeptidase complex mutant obscurin premature protein degradation research study skeletal ubiquitin-protein ligase

项目摘要

7. Project Summary/Abstract Cullin mediated protein turnover in skeletal and cardiac muscles The regulated degradation of proteins is an important mechanism for the survival of cells. Accumulation of undegraded proteins in aggrosomes/inclusion bodies, or the premature degradation of (mutant) proteins is often associated with development of diseases, like cardiac and skeletal muscle myopathies. Cardiac and skeletal muscle cells contain up to four proteolytic systems for the degradation of myofbrillar proteins: the caspase and calpain proteases, the ubiquitin-proteasome system (UPS), and the autophagy system. Degradation of most cellular proteins is achieved by way of the UPS and requires tagging of substrate proteins by ubiquitin (poly-ubiquitylation) through an enzymatic cascade. Recognition of substrate and its subsequent ubiquitylation involves the concerted action of E3-ubiquitin ligases and E2-ubiquitin conjugating enzymes. Intriguingly, several components involved in the ubiquitylation of muscle proteins are localized along myofibrils, like the muscle specific E3-ligases of the MuRF protein family. While considerable attention has been focused on these muscle specific UPS components, there is limited information on the role of the more ubiquitously expressed E3-ligases in muscle protein turnover, and whether they may play a more causal role for the development and progression of myopathies. While investigating the obscurin family of myofibrillar proteins, we identified several previously uncharacterized links to cullin-RING proteins, a large family of ubiquitin E3-ligases. Moreover we found that some of these cullin proteins exhibit a myofibrillar localization, comparable to muscle specific E3-ligases. These intriguing results, and the observation that cullin-RING ligases are altered in models for dilated cardiomyopathy (MLP knockout mouse) and skeletal muscle myopathy (obscurin knockout) led us to the hypothesis that cullin-3 and its associated proteins may play a greater role for muscle protein turnover than previously anticipated. The proposed research project investigates the biological role of cullin proteins for muscle specific protein- turnover, and their links to myofibrillar proteins of the obscurin protein family, through a combination of in vivo approaches that analyze cardiac and skeletal muscle physiology and function, with in vitro methods that characterize cullin-3, its binding partners, and their association to obscurin proteins at the molecular level. Preliminary studies indicate that results from this project may have ramifications not only for skeletal muscle myopathies, like the limb-girdle muscular dystrophy (type 2J) through links with obscurin proteins, but also for cardiomyopathies, since cullin proteins, and some of their binding partners are significantly altered in animal models for dilated cardiomyopathy (MLP knockout).

7. 项目总结/文摘