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Hsp40 and Hsp70 in Membrane Protein Triage

膜蛋白分类中的 Hsp40 和 Hsp70

基本信息

批准号：
10718226
负责人：
DOUGLAS M CYR
金额：
$ 42.23万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718226
关键词：
ATP phosphohydrolase ATP-Binding Cassette Transporters Adopted Amyloid Attention Autophagocytosis Autophagosome Benign Binding Biochemical Biogenesis Biological Assay Biosynthetic Proteins Blindness Cell Survival Cell physiology Cells Client Complex Cystic Fibrosis Cytoplasm Cytosol Data Detergents Diameter Disease Distal Docking Endoplasmic Reticulum Ensure Event Exhibits Experimental Designs Face G-Protein-Coupled Receptors Goals Health Human Image Induction of Apoptosis Inferior Inherited Intermediate resistance Interstitial Lung Diseases Kinetics Klinefelter&apos s Syndrome Length Light Location Lysosomes Maintenance Membrane Membrane Protein Traffic Membrane Proteins Microtubules Missense Mutation Molecular Chaperones Movement Mutate Paint Peptides Phosphatidylinositols Phosphotransferases Poison Process Proteins Proteome Pulmonary Fibrosis Quality Control Resistance Retinitis Pigmentosa Role Series Shapes Side Site Surface System Testing Thermodynamics Triage Tubular formation WD Repeat Work Yeasts cell motility conformer experimental study farnesylation human disease live cell imaging lysosomal proteins lysosome membrane man meter misfolded protein multicatalytic endopeptidase complex mutant non-Native polypeptide premature prevent protein aggregation protein degradation protein folding protein misfolding proteotoxicity receptor receptor function recruit restraint screening therapy development ubiquitin-protein ligase

项目摘要

Project Summary: Membrane protein (MP) biogenesis begins in the endoplasmic reticulum (ER) and is a complex process, as domains on both sides of the ER membrane, and within the membrane bilayer, must fold and assemble. MPs understudy include ABC-Transporters, P-Type ATPases, G-protein coupled receptors, and BRICHOS proteins. Missense mutations that cause misfolding and premature degradation of MPs give rise to diseases such as cystic fibrosis, hypogonadotropic hypogonadism, retinitis pigmentosa and idiopathic lung fibrosis. In order to prevent toxic accumulation, misfolded MPs are targeted for ER-associated degradation (ERAD) by E3 ubiquitin ligase complexes. The ER transmembrane Hsp40 DNAJB12 (JB12) recruits cytosolic Hsp70 to the cytoplasmic face of the ER and together these chaperones deliver the misfolded MPs to ERAD machinery. In order for a misfolded protein to be a candidate for ERAD however, it must be competent for extraction from the confines of the ER membrane and delivered to the cytosolic proteasome. Misfolded proteins with structural restraints that prevent entrance into the proteasome necessitate an alternative quality control mechanism to ensure degradation. Misfolded MPs expose surfaces in the ER lumen, membrane, and the cytosol, so the coordinated action of ERQC factors in different locations manage this challenge. Mistakes in MP protein management are fatal when rogue clients adopt a toxic shape that enable rogues to damage membranes and dominantly poison essential cell functions. Hsp70 and Hsp40s act with folding and degradation machines to triage MPs. They shield against proteotoxicity through suppressing aggregation, refolding clients, selection of clients for degradation and regulating flux though protein biosynthetic systems. A major problem to ERQC systems are the MPs that accumulate in thermodynamically stable intermediate states that are non-native and self-associate to form oligomers, amorphous aggregates, and amyloid-like fibrils. Such misfolded conformers bury surfaces that are normally recognized by ERQC factors, and their thermodynamic stability hinders the unfolding events required for their extraction from membranes and degradation in the narrow central cavity of the proteasome. Thermodynamically stable MP intermediates are resistant to ERAD and we discovered that they are degraded by a JB12 dependent ER-phagy mechanism. The overall goal of the experiments included in this proposal is to define nodes of cross-talk between the Hsp70 chaperone system, ERAD and ER-phagy that are essential for cell viability and proteome maintenance.

项目总结: