γ-分泌酶/底物相互作用的单分子动力学研究以及 AD 引起的突变的影响-猫眼课题宝

γ-分泌酶/底物相互作用的单分子动力学研究以及 AD 引起的突变的影响

批准号：

10323672

负责人：

Scott Thomas Forth

金额：

$19.27万

依托单位：

RENSSELAER POLYTECHNIC INSTITUTE

依托单位国家：

美国

项目类别：

财政年份：

2021

资助国家：

美国

项目状态：

已结题

起止时间：

2021-01-15 至 2023-12-31

来源：

https://reporter.nih.gov/project-details/10323672

关键词：

Active Sites Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Aspartate Benign Binding Biochemical Biological Assay Brain C-terminal Carboxypeptidase Catalytic Domain Complex Coupled Dementia Docking Dyes Enzyme Interaction Enzyme Kinetics Enzymes Experimental Designs Fluorescence Generations Homologous Gene Immobilization Individual Integral Membrane Protein Kinetics Lipid Bilayers Liposomes Measurement Measures Mediating Membrane Methods Micelles Microscope Monitor Mutation Pathologic Peptide Fragments Peptide Hydrolases Process Production Proteolysis Public Health Senile Plaques Substrate Interaction Techniques Time Total Internal Reflection Fluorescent Transmembrane Domain United States beta pleated sheet beta secretase disease-causing mutation drug discovery early onset enzyme substrate familial Alzheimer disease gamma secretase hydrophilicity insight mutant neurotoxic novel presenilin protein complex single molecule

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英文摘要

Project Summary Amyloid plaque, composed of amyloid-b peptide (Ab), is a pathological hallmark of Alzheimer’s disease (AD). g-secretase is responsible for the cleavage of C99, the C-terminal fragment of 99 residues of amyloid precursor protein (APP), to generate Ab. Previous kinetics studies of g- secretase measured the final production of APP intracellular domain (AICD) and/or Ab. However, the kinetics rates for individual steps of the generation of Ab from C99 are lacking. Here we will use single molecule fluorescence studies to observe enzyme/substrate molecules in real time, and measure the kinetics of enzyme/substrate association and cleavage in g- secretase-mediated intramembrane proteolysis to generate Ab (Aim1), and determine how familial AD (FAD) mutations alter the kinetics of enzyme/substrate association and cleavage in AD (Aim2).

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