Navigating the dynamic landscape of alpha-synuclein morphology: a review of the physiologically relevant tetrameric conformation  

作　　者：Heather R.Lucas Ricardo D.Fernández 

机构地区：[1]Department of Chemistry, Virginia Commonwealth University

出　　处：《Neural Regeneration Research》2020年第3期407-415,共9页中国神经再生研究（英文版）

基　　金：supported in part by Award No.18-7(to HRL)from the Commonwealth of Virginia’s Alzheimer’s and Related Diseases Research Award Fund,administered by the Virginia Center on Aging

摘　　要：N-acetylatedα-synuclein(αSyn)has long been established as an intrinsically disordered protein associated with a dysfunctional role in Parkinson’s disease.In recent years,a physiologically relevant,higher order conformation has been identified as a helical tetramer that is tailored by buried hydrophobic interactions and is distinctively aggregation resistant.The canonical mechanism by which the tetramer assembles remains elusive.As novel biochemical approaches,computational methods,pioneering purification platforms,and powerful imaging techniques continue to develop,puzzling information that once sparked debate as to the veracity of the tetramer has now shed light upon this new counterpart inαSyn neurobiology.Nuclear magnetic resonance and computational studies on multimericαSyn structure have revealed that the protein folding propensity is controlled by small energy barriers that enable large scale reconfiguration.Alternatively,familial mutations ablate tetramerization and reconfigure polymorphic fibrillization.In this review,we will discuss the dynamic landscape ofαSyn quaternary structure with a focus on the tetrameric conformation.N-acetylated α-synuclein(αSyn) has long been established as an intrinsically disordered protein associated with a dysfunctional role in Parkinson’s disease. In recent years, a physiologically relevant, higher order conformation has been identified as a helical tetramer that is tailored by buried hydrophobic interactions and is distinctively aggregation resistant. The canonical mechanism by which the tetramer assembles remains elusive. As novel biochemical approaches, computational methods, pioneering purification platforms, and powerful imaging techniques continue to develop, puzzling information that once sparked debate as to the veracity of the tetramer has now shed light upon this new counterpart in αSyn neurobiology. Nuclear magnetic resonance and computational studies on multimeric αSyn structure have revealed that the protein folding propensity is controlled by small energy barriers that enable large scale reconfiguration. Alternatively, familial mutations ablate tetramerization and reconfigure polymorphic fibrillization. In this review, we will discuss the dynamic landscape of αSyn quaternary structure with a focus on the tetrameric conformation.

关 键 词：ALPHA-SYNUCLEIN amyloid FIBRILS intrinsically disordered PROTEIN MULTIMER N-ACETYLATION oligomer Parkinson’s disease PROTEIN folding PROTEIN structure TETRAMER 

分 类 号：R73[医药卫生—肿瘤]