Molecular aspects of copper binding to the prion protein

铜与朊病毒蛋白结合的分子方面

基本信息

批准号：
8634797
负责人：
GLENN L MILLHAUSER
金额：
$ 27.01万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634797
关键词：
Affinity Age of Onset Alzheimer&apos s Disease Amino Acid Sequence Apoptosis Apoptotic Behavior Binding Birds Bovine Spongiform Encephalopathy Brain C-terminal Cellular Stress Cellular Structures Chemistry Cleaved cell Complex Copper Creutzfeldt-Jakob Syndrome Deposition Deterioration Disease Dissociation Dominant-Negative Mutation Environment Event Funding Glycoproteins Goat Health Homeostasis Human In Vitro Infectious Agent Inherited Ions Ischemic-Hypoxic Encephalopathy Kuru Laboratories Lead Length Lesion Link Magnetic Resonance Maintenance Mammals Measurement Membrane Metal Ion Binding Metalloproteins Metals Micronutrients Molecular Molecular Conformation Mutation N-terminal Neuraxis Neurodegenerative Disorders Neurons Parkinson Disease Pathology Peptide Sequence Determination Phase Physiological Play Polysaccharides PrP Prion Diseases Prions Process Protein Glycosylation Proteins Recombinant Proteins Regulation Research Role Scrapie Sheep Site Spin Labels Structure Surface Technology Tertiary Protein Structure Testing Thermodynamics Thinking Tissues Traumatic Brain Injury Work Zinc age related design extracellular glycosylation in vivo mutant nervous system disorder neurochemistry neuroprotection novel prevent programs protein misfolding public health relevance relating to nervous system research study theories unpublished works uptake

项目摘要

DESCRIPTION (provided by applicant): The objective of this research program is to elucidate, at the molecular level, the mechanism and function of copper and zinc binding in the prion protein (PrP) and the relationship of these interactions to neuron maintenance and neurological disease. A misfolded form of the prion protein (PrP) is responsible for a class of fatal neurodegenerative diseases termed the Transmissible Spongiform Encephalopathies (TSEs), which include mad cow disease and Creutzfeldt-Jakob disease in humans. PrP is a highly abundant, membrane-bound glycoprotein found in all mammals and avian species. Although originally recognized for its role in neurodegenerative disease, it is now clear that PrP is essential for sustaining neuron function and regulating apoptosis. PrP takes up both copper and zinc at sites are essential for PrP activity. Over the last funding period, the PI's laboratory characterized structural and thermodynamic features of these metal ion sites and also identified a remarkable link between certain mutations and onset age in inherited prion disease. The next funding period will build on these findings using both magnetic resonance and cellular studies with the following projects: 1) determine the structure of the full-length, copper or zinc occupied protein; 2) evaluate how metal ions influence in vivo cleavage, implicated in apoptosis regulation; and 3) examine how structure and cellular behavior is altered by mutations associated with inherited disease, and also by mutations that prevent disease. Moreover, project three will apply new synthetic strategies for investigating the role of protein glycosylation. It is anticipated that these studies will provide fundamental new concepts for understanding the role of both PrP and copper in basic neurochemistry, and strategies for treating neurodegenerative disease and brain trauma.

描述（由申请人提供）：该研究计划的目的是在分子水平上阐明铜和锌结合在prion蛋白（PRP）中的机制和功能，以及这些相互作用与神经元维持和神经疾病的关系。 prion蛋白（PRP）的一种错误折叠的形式是导致一类称为可传染性海绵状脑病（TSE）的致命神经退行性疾病，其中包括人类中的疯牛病和Creutzfeldt-Jakob病。 PRP是在所有哺乳动物和禽类中发现的一种高度丰富的膜结合糖蛋白。尽管最初以其在神经退行性疾病中的作用而被认可，但现在很明显，PRP对于维持神经元功能和调节凋亡至关重要。 PRP在位置占用铜和锌对于PRP活动至关重要。在上一个资金期间，PI的实验室表征了这些金属离子位点的结构和热力学特征，并且还确定了在遗传病毒疾病中某些突变与发病年龄之间的显着联系。下一个资金期将使用以下项目的磁共振和细胞研究以这些发现为基础：1）确定全长，铜或锌占据蛋白质的结构； 2）评估金属离子如何影响体内切割，与凋亡调节有关； 3）检查结构和细胞行为如何通过与遗传疾病相关的突变以及预防疾病的突变改变。此外，第三项目将采用新的合成策略来研究蛋白质糖基化的作用。预计这些研究将为理解PRP和铜在基本神经化学中的作用以及治疗神经退行性疾病和脑部创伤的策略提供基本的新概念。