In situ single-molecule investigations of the impacts of biochemical perturbations on conformational intermediates of monomeric α-synuclein

Huang，Wenmao1,2; Liu，Jingzhun3; Le，Shimin1,4; Yao，Mingxi3,5; Shi，Yi6; Yan，Jie1,3,7

2024-03-01

10.1063/5.0188714

APL Bioengineering   影响因子和分区

2473-2877

α-Synuclein aggregation is a common trait in synucleinopathies, including Parkinson's disease. Being an unstructured protein, α-synuclein exists in several distinct conformational intermediates, contributing to both its function and pathogenesis. However, the regulation of these monomer conformations by biochemical factors and potential drugs has remained elusive. In this study, we devised an in situ single-molecule manipulation approach to pinpoint kinetically stable conformational intermediates of monomeric α-synuclein and explore the effects of various biochemical factors and drugs. We uncovered a partially folded conformation located in the non-amyloid-β component (NAC) region of monomeric α-synuclein, which is regulated by a preNAC region. This conformational intermediate is sensitive to biochemical perturbations and small-molecule drugs that influencing α-synuclein's aggregation tendency. Our findings reveal that this partially folded intermediate may play a role in α-synuclein aggregation, offering fresh perspectives for potential treatments aimed at the initial stage of higher-order α-synuclein aggregation. The single-molecule approach developed here can be broadly applied to the study of disease-related intrinsically disordered proteins.

SCI ; EI

英语

其他

2-s2.0-85186691931

Scopus

1.Department of Physics,National University of Singapore,Singapore,117542,Singapore
2.Department of Chemical Biology,School of Chemistry and Chemical Engineering,Shanghai Jiao Tong University,Shanghai,200240,China
3.Mechanobiology Institute,National University of Singapore,Singapore,117411,Singapore
4.Research Institute for Biomimetics and Soft Matter,Fujian Provincial Key Lab for Soft Functional Materials Research,Department of Physics,Xiamen University,Xiamen,361005,China
5.Department of Biomedical Engineering,Southern University of Science and Technology,Shenzhen,518055,China
6.School of Chemistry and Molecular Engineering,East China Normal University,Shanghai,200241,China
7.Centre for Bioimaging Sciences,National University of Singapore,Singapore,117546,Singapore

Huang，Wenmao,Liu，Jingzhun,Le，Shimin,et al. In situ single-molecule investigations of the impacts of biochemical perturbations on conformational intermediates of monomeric α-synuclein[J]. APL Bioengineering,2024,8(1).

Huang，Wenmao,Liu，Jingzhun,Le，Shimin,Yao，Mingxi,Shi，Yi,&Yan，Jie.(2024).In situ single-molecule investigations of the impacts of biochemical perturbations on conformational intermediates of monomeric α-synuclein.APL Bioengineering,8(1).

Huang，Wenmao,et al."In situ single-molecule investigations of the impacts of biochemical perturbations on conformational intermediates of monomeric α-synuclein".APL Bioengineering 8.1(2024).