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Understanding GABAA receptor protein folding and misfolding

了解 GABAA 受体蛋白折叠和错误折叠

基本信息

批准号：
10383160
负责人：
Tingwei Mu
金额：
$ 35.18万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383160
关键词：
ATF6 gene Aging Biogenesis Brain Calnexin Cell membrane Cell surface Cells Cellular biology Complex Data Degradation Pathway Disease ERp57 Electrophysiology (science)Electrostatics Endoplasmic Reticulum Environment Enzymes Epilepsy Equilibrium Genes Genetic Glycoproteins Goals Human Hydrophobicity Inherited Ion Channel Ion Channel Gating Ion Channel Protein Lead Lesion Maps Mediating Membrane Missense Mutation Molecular Molecular Chaperones Mutation Neuraxis Neurons Neurotransmitters Nicotinic Receptors Pathogenicity Pathway interactions Pharmacological Treatment Polysaccharides Proteins Proteome Proteomics Publications RIPK1 gene Research Role Site Stress Syndrome Testing Ubiquitination base disease-causing mutation disulfide bond experimental study gamma-Aminobutyric Acid genetic linkage glycosylation high throughput screening loss of function mutant neural circuit novel novel strategies overexpression protein folding protein misfolding proteostasis receptor receptor function response small molecule tandem mass spectrometry trafficking transcription factor zinc-binding protein

项目摘要

Project Description Proteostasis, an optimal state of the cellular proteome, is constantly challenged by intrinsic stress, such as inherited misfolding-prone proteins, environment, and aging. Proteostasis deficiency in ion channels leads to a variety of ion channel diseases called channelopathies, which are often caused by excessive endoplasmic reticulum-associated degradation (ERAD) and inefficient membrane trafficking of corresponding ion channel proteins harboring misfolding-prone mutations. We use gamma- aminobutyric acid type A (GABAA) receptors, the primary inhibitory neurotransmitter-gated ion channels in the mammalian central nervous systems, as a representative ion channel, to elucidate their folding and ERAD pathway in the endoplasmic reticulum (ER). The interaction between GABAA receptors and a network of proteins in cells is critical to maintain the folding, degradation, trafficking, and thus function of GABAA receptors. However, the molecular mechanism of maintaining GABAA receptor proteostasis is not well understood. Idiopathic epilepsy has a strong genetic linkage to loss of function of GABAA receptors. We focus on studying missense mutations that lead to misfolding, extensive degradation, and thus loss of function of mutant GABAA receptors. Our long term goal is to perform a detailed molecular mechanism study to elucidate how the folding, assembly, degradation of GABAA receptors are regulated in cells and use the principles acquired to correct epilepsy-associated misfolded GABAA receptors. Here, in Specific Aim 1, we aim to elucidate a coordinated engagement of chaperones and folding enzymes in directing the folding of GABAA receptors in the ER. In Specific Aim 2, we aim to determine the ERAD pathway of misfolding-prone mutant GABAA receptors. In Specific Aim 3, we propose to remodel the ER proteostasis network to correct the misfolding and function of pathogenic GABAA receptors. This proposed research will provide proof-of-principle cases about restoring proteostasis to ameliorate genetic epilepsy resulting from GABAA receptor misfolding.

项目描述