Molecular structures of tau aggregates studied by solid-state NMR

通过固态核磁共振研究 tau 聚集体的分子结构

基本信息

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
起止时间：
2018-08-15 至 2023-07-31
项目状态：
已结题

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

项目摘要

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

项目概要 Tau 是一种本质上无序的微管相关蛋白，其错误折叠成不溶性的丝状聚集体是阿尔茨海默氏症的两个标志之一。神经原纤维缠结被过度磷酸化，但磷酸化如何转变 tau 的功能我们建议在分子水平上尚未充分了解其功能失调的原纤维结构。通过研究 tau 富含脯氨酸区域的结构动力学来扩展母体资助。该区域已被认为在微管结合中发挥重要作用，并且已知包含我们将研究这个富含脯氨酸的结构域如何改变它的许多过度磷酸化位点。与微管结合后的构象和动力学，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。富含脯氨酸的肽在游离和结合状态下的固态核磁共振谱图从这项研究中获得的分子见解将被纳入我们的研究中。父授权中的全长 tau。 1

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Microtubule-binding core of the tau protein.

DOI：
10.1126/sciadv.abo4459
发表时间：
2022-07-22
期刊：
Science advances
影响因子：
13.6
作者：
通讯作者：

NMR structure verifies the eponymous zinc finger domain of transcription factor ZNF750.

DOI：
10.1016/j.yjsbx.2023.100093
发表时间：
2023-12
期刊：
JOURNAL OF STRUCTURAL BIOLOGY-X
影响因子：
2.9
作者：
Rua, Antonio J.;Whitehead, Richard D.;Alexandrescu, Andrei T.
通讯作者：
Alexandrescu, Andrei T.

Amyloid fibril structures of tau: Conformational plasticity of the second microtubule-binding repeat.

DOI：
10.1126/sciadv.adh4731
发表时间：
2023-07-14
期刊：
SCIENCE ADVANCES
影响因子：
13.6
作者：
El Mammeri, Nadia;Duan, Pu;Dregni, Aurelio J.;Hong, Mei
通讯作者：
Hong, Mei

Structures of AT8 and PHF1 phosphomimetic tau: Insights into the posttranslational modification code of tau aggregation.

AT8 和 PHF1 拟磷 tau 的结构：深入了解 tau 聚集的翻译后修饰代码。

DOI：
10.1073/pnas.2316175121
发表时间：
2024
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Mammeri,NadiaEl;Dregni,AurelioJ;Duan,Pu;Hong,Mei
通讯作者：
Hong,Mei

Hydration and Dynamics of Full-Length Tau Amyloid Fibrils Investigated by Solid-State Nuclear Magnetic Resonance.