翻译后修饰调控神经退行性疾病相关蛋白质聚集体的构象多态性研究  

Post-translational modifications regulate conformational polymorphism of protein aggregates associated with neurodegenerative diseases

作　　者：王若楠 简中意 于兰兰 王晨轩[1] Ruonan Wang;Zhongyi Jian;Lanlan Yu;Chenxuan Wang(State Key Laboratory of Common Mechanism Research for Major Disease,Department of Biophysics and Structural Biology,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,Peking Union Medical College,Beijing 100005,China)

机构地区：[1]中国医学科学院基础医学研究所,北京协和医学院基础学院,生物物理及结构生物学系,重大疾病共性机制研究全国重点实验室,北京1000

出　　处：《中国科学:化学》2025年第4期785-807,共23页SCIENTIA SINICA Chimica

基　　金：国家自然科学基金(编号:92353302)资助项目。

摘　　要：淀粉样蛋白质聚集体的构象多态性在神经退行性疾病的发病机制及靶向药物研发中具有重要意义.构象多态性是淀粉样蛋白聚集体的基本结构特征且受多种因素调控.翻译后修饰作为关键的调控因子,通过调节淀粉样蛋白的聚集动力学与聚集体结构,赋予聚集体丰富的构象多态性.本文回顾了近年来为解析淀粉样蛋白聚集体构象多态性发展的高分辨率结构解析新方法,介绍了淀粉样蛋白聚集体构象多态性的结构特征与调控机制研究取得的新进展.本文总结了淀粉样蛋白翻译后修饰的异质化效应及其在神经退行性疾病病理机制中发挥的关键作用,阐明翻译后修饰对淀粉样聚集体构象多态性重要的调控机制,并分析了现阶段该研究领域的局限性与挑战.The conformational polymorphism of amyloid aggregates is of great significance in the pathogenesis of neurodegenerative diseases and the development of targeted drugs.Conformational polymorphism is the basic structural feature of amyloid aggregates and regulated by multiple factors.Among them,post-translational modification,as a key regulatory factor,endows aggregates with rich conformational diversity by regulating the aggregation dynamics and aggregate structure of amyloid.Here we review the new high-resolution structural analysis methods developed in recent years to analyze the conformational polymorphism of amyloid aggregates,and introduce the new progress in the study of the structural characteristics and regulatory mechanisms of the conformational polymorphism of amyloid aggregates.This review summarizes the heterogeneous effects of amyloid post-translational modifications and their key role in the pathological mechanisms of neurodegenerative diseases,illustrates the important regulatory mechanisms of posttranslational modifications on the conformational polymorphism of amyloid aggregates,and analyzes the limitations and challenges of this research field at this stage.

关 键 词：淀粉样蛋白 聚集 异质化效应 构象多态性 结构解析 

分 类 号：R741[医药卫生—神经病学与精神病学]