通过固态核磁共振研究 tau 聚集体的分子结构-猫眼课题宝

通过固态核磁共振研究 tau 聚集体的分子结构

批准号：

10230898

负责人：

Mei Hong

金额：

$32.18万

依托单位：

MASSACHUSETTS INSTITUTE OF TECHNOLOGY

依托单位国家：

美国

项目类别：

财政年份：

2018

资助国家：

美国

项目状态：

已结题

起止时间：

2018-08-15 至 2023-07-31

来源：

https://reporter.nih.gov/project-details/10230898

关键词：

Alzheimer&apos s Disease American Amino Acid Sequence Antibodies Applications Grants Binding Biochemical Brain Cells Chemicals Cryoelectron Microscopy Data Disease Electrostatics Epitopes Equilibrium Event Exhibits Filament Genetic Polymorphism Grant Image Investigation Label Length Maps Measures Methods Microtubule-Associated Proteins Microtubules Molecular Molecular Conformation Molecular Structure N-terminal NMR Spectroscopy Negative Staining Neurodegenerative Disorders Neurofibrillary Tangles Neurons P2 peptide Paper Patients Peptides Phosphorylation Phosphorylation Site Play Process Progressive Supranuclear Palsy Proline Proline-Rich Domain Protein Isoforms Protein Region Proteins Publishing Resolution Role Shapes Site Structural Models Structure Tauopathies Testing Tubulin chronic traumatic encephalopathy design insight misfolded protein molecular dynamics monomer parent grant polyproline prion-like protein aggregation protein misfolding seryl-proline small molecule inhibitor solid state nuclear magnetic resonance tau Proteins tau aggregation

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中文摘要

翻译

项目摘要 Tau是一种内在无序的微管相关蛋白，其错误折叠成不溶性蛋白，丝状聚集体是阿尔茨海默病的两个标志之一。在AD大脑中，神经元缠结是过度磷酸化的，但磷酸化如何将tau蛋白的功能在分子水平上还没有很好地理解其功能失调的原纤维结构。我们建议通过研究tau富含脯氨酸区域的结构动力学来扩展母基金。这区域已经被暗示在微管结合中起重要作用，并且已知包含 tau蛋白的许多过度磷酸化位点。我们将研究这个富含脯氨酸的结构域如何改变其构象和动力学结合微管，以及磷酸化如何调节结合平衡和构象平衡。我们将通过测量获得这些信息在没有和有下，游离和结合状态的富含脯氨酸的肽的固态NMR光谱磷酸化从这项研究中获得的分子见解将被整合到我们的研究中，在父母补助金中的全长tau。 1

英文摘要

Project Summary Tau is an intrinsically disordered microtubule-associated protein whose misfolding into insoluble filamentous aggregates is one of the two hallmarks of Alzheimer’s disease. In AD brains the tau neurofibrillary tangles are hyperphosphorylated, but how phosphorylation converts tau’s functional structure to its dysfunctional fibril structure is not well understood at the molecular level. We propose to extend the parent grant by investigating the structural dynamics of a proline-rich region of tau. This region has been implicated to play a significant role in microtubule binding and is known to contain many hyperphosphorylation sites of tau. We will study how this proline-rich domain changes its conformation and dynamics upon binding to microtubules, and how phosphorylation regulates the binding equilibrium and the conformational equilibrium. We will obtain this information by measuring solid-state NMR spectra of the proline-rich peptide in the free and bound states without and with phosphorylation. Molecular insights gained from this study will be integrated into our investigation of the full-length tau in the parent grant. 1

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