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

IF 6.6 3区 医学 Q1 ENGINEERING, BIOMEDICAL
Wenmao Huang, Jingzhun Liu, Shimin Le, Mingxi Yao, Yi Shi, Jie Yan
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引用次数: 0

Abstract

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.

原位单分子研究生化扰动对单体α-突触核蛋白构象中间产物的影响。
α-突触核蛋白聚集是包括帕金森病在内的突触核蛋白病的常见特征。作为一种非结构化蛋白质,α-突触核蛋白存在几种不同的构象中间体,对其功能和发病机制都有影响。然而,生化因素和潜在药物对这些单体构象的调控仍然难以捉摸。在这项研究中,我们设计了一种原位单分子操作方法来精确定位α-突触核蛋白单体的动力学稳定构象中间体,并探索各种生化因素和药物的影响。我们发现了位于单体α-突触核蛋白非淀粉样β成分(NAC)区域的部分折叠构象,该构象受到前NAC区域的调控。这种构象中间体对影响α-突触核蛋白聚集倾向的生化扰动和小分子药物很敏感。我们的研究结果表明,这种部分折叠的中间体可能在α-突触核蛋白聚集中发挥作用,为针对高阶α-突触核蛋白聚集初期的潜在治疗提供了新的视角。本文开发的单分子方法可广泛应用于与疾病相关的内在无序蛋白的研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
APL Bioengineering
APL Bioengineering ENGINEERING, BIOMEDICAL-
CiteScore
9.30
自引率
6.70%
发文量
39
审稿时长
19 weeks
期刊介绍: APL Bioengineering is devoted to research at the intersection of biology, physics, and engineering. The journal publishes high-impact manuscripts specific to the understanding and advancement of physics and engineering of biological systems. APL Bioengineering is the new home for the bioengineering and biomedical research communities. APL Bioengineering publishes original research articles, reviews, and perspectives. Topical coverage includes: -Biofabrication and Bioprinting -Biomedical Materials, Sensors, and Imaging -Engineered Living Systems -Cell and Tissue Engineering -Regenerative Medicine -Molecular, Cell, and Tissue Biomechanics -Systems Biology and Computational Biology
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