Solid-state NMR Structural Characterizations of Polymorphic Transthyretin Amyloids

多态性运甲状腺素蛋白淀粉样蛋白的固态 NMR 结构表征

• 批准号: 10164870
• 负责人: KWANG HUN LIM
• 金额: $ 21.91万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164870
• 关键词: Adopted; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloidosis; Biological; Biological Markers; Collaborations; Degenerative Disorder; Deposition; Disease; Docking; Exhibits; Goals; Human; Hydrophobicity; Label; Letters; Link; Molecular; Molecular Conformation; Mutation; Parkinson Disease; Pathogenicity; Pathway interactions; Phenotype; PrP; Prealbumin; Prion Diseases; Prions; Process; Proteins; Research; Resolution; Scheme; Structural Models; Structure; Testing; Therapeutic Agents; Tissues; Variant; alpha synuclein; amyloid formation; amyloid structure; beta pleated sheet; biophysical analysis; conformational conversion; disease phenotype; flexibility; human disease; improved; innovation; insight; interest; interfacial; intermolecular interaction; monomer; mutant; non-prion; polypeptide; prevent; programs; protein aggregation; protein folding; protein function; protein misfolding; simulation; solid state nuclear magnetic resonance; therapeutically effective; three dimensional structure; tissue degeneration; tool

Protein misfolding and amyloid formation is implicated in numerous diseases such as amyloidoses, prion and Alzheimer's diseases. Prion disease is unique in that the natively folded prion protein forms aggregates with distinct molecular conformations (prion strains), which underlie different disease phenotypes.1-3 The prion strain may be encoded in the primary sequence and mutations of the protein induce different strains, causing distinct disease phenotypes. Recent studies have suggested the strain hypothesis is applicable to other amyloid diseases that also manifest diverse disease phenotypes.1,2,4,5 Nonprion amyloids were shown to exhibit a wide conformational diversity,6-10 which may be linked to the phenotype variations. However, little is known about molecular basis of the diverse misfolding pathways and structural diversity of amyloid. Structural studies of the amyloid are essential to understanding molecular mechanism of amyloid diversity. Effect of the pathogenic mutations on misfolding pathway should also be examined. The systematic biophysical studies have, however, been challenging for previously investigated amyloidogenic proteins due to the limited number of pathogenic mutations associated with distinct disease phenotypes. In addition, the most extensively studied polypeptides, β-amyloid and α-synuclein associated with Alzheimer's and Parkinson's diseases respectively, are natively unfolded, rendering the polypeptides not amenable for mechanistic studies of the initial conformational transition (misfolding). This research program is aimed at investigating amyloid formation mechanisms of a natively folded protein, transthyretin (TTR), using solid-state NMR. Transthyretin (TTR) is one of more than 30 human proteins that undergo an aberrant conformational change and misassemble into β-structured amyloid. Amyloid formation of wild type and more than 100 mutant forms of TTR are known to cause various amyloidoses with enormous phenotype diversity.11 The main hypothesis of this proposal is that pathogenic mutant forms of TTR may have distinct misfolding pathways, adopting diverse amyloid conformations with different toxic activities, which may result in diverse disease phenotypes and tissue-selective depositions. The hypothesis will be tested through the structural characterization of amyloid derived from wild-type and various pathogenic mutant forms of TTR. In particular, solid-state NMR with innovative labeling schemes will provide valuable insights into amyloid diversity. Specific aims of the proposal are to explore: (1) Native-like structural features of amyloid core regions. (2) Conformational changes of the loop regions during amyloid formation. (3) Quaternary structure of WT and mutant forms of TTR amyloid. Mechanistic understanding of the misfolding and amyloid formation pathways would be critical to developing effective therapeutic strategies for TTR amyloidoses.

蛋白质错误折叠和淀粉样蛋白形成与许多疾病有关，如淀粉样变性，

项目成果

Toxic Misfolded Transthyretin Oligomers with Different Molecular Conformations Formed through Distinct Oligomerization Pathways.

• DOI: 10.1021/acs.biochem.2c00390
• 发表时间: 2022-11-01
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Dasari, Anvesh K. R.;Yi, Sujung;Coats, Matthew F.;Wi, Sungsool;Lim, Kwang Hun
• 通讯作者: Lim, Kwang Hun

CD and Solid-State NMR Studies of Low-Order Oligomers of Transthyretin.

• DOI: 10.1007/978-1-0716-2597-2_21
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)