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Article Dans Une Revue ACS Chemical Neuroscience Année : 2018

From a Highly Disordered to a Metastable State: Uncovering Insights of alpha-Synuclein

Résumé

alpha-Synuclein (alphaS) is a major constituent of Lewy bodies, the insoluble aggregates that are the hallmark of one of the most prevalent neurodegenerative disorders, Parkinson's disease (PD). The vast majority of experiments in vitro and in vivo provide extensive evidence that a disordered monomeric form is the predominant state of alphaS in water solution, and it undergoes a large-scale disorder-to-helix transition upon binding to vesicles of different types. Recently, another form, tetrameric, of alphaS with a stable helical structure was identified experimentally. It has been shown that a dynamic intracellular population of metastable alphaS tetramers and monomers coexists normally; and the tetramer plays an essential role in maintaining alphaS homeostasis. Therefore, it is of interest to know whether the tetramer can serve as a means of preventing or delaying the start of PD. Before answering this very important question, it is, first, necessary to find out, on an atomistic level, a correlation between tetramers and monomers; what mediates tetramer formation and what makes a tetramer stable. We address these questions here by investigating both monomeric and tetrameric forms of alphaS. In particular, by examining correlations between the motions of the side chains and the main chain, steric parameters along the amino-acid sequence, and one- and two-dimensional free-energy landscapes along the coarse-grained dihedral angles gamma and delta and principal components, respectively, in monomeric and tetrameric alphaS, we were able to shed light on a fundamental relationship between monomers and tetramers, and the key residues involved in mediating formation of a tetramer. Also, the reasons for the stability of tetrameric alphaS and inability of monomeric alphaS to fold are elucidated here.

Dates et versions

hal-03691239 , version 1 (08-06-2022)

Identifiants

Citer

Yoann Cote, P Delarue, H Scheraga, P Senet, G Maisuradze. From a Highly Disordered to a Metastable State: Uncovering Insights of alpha-Synuclein. ACS Chemical Neuroscience, 2018, 9 (5), pp.1051-1065. ⟨10.1021/acschemneuro.7b00446⟩. ⟨hal-03691239⟩
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