Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Int J Mol Sci. 2024 Aug 1;25(15):8399. doi: 10.3390/ijms25158399.
In this work, we explored the intrinsic disorder status of the three members of the synuclein family of proteins-α-, β-, and γ-synucleins-and showed that although all three human synucleins are highly disordered, the highest levels of disorder are observed in γ-synuclein. Our analysis of the peculiarities of the amino acid sequences and modeled 3D structures of the human synuclein family members revealed that the pathological mutations A30P, E46K, H50Q, A53T, and A53E associated with the early onset of Parkinson's disease caused some increase in the local disorder propensity of human α-synuclein. A comparative sequence-based analysis of the synuclein proteins from various evolutionary distant species and evaluation of their levels of intrinsic disorder using a set of commonly used bioinformatics tools revealed that, irrespective of their origin, all members of the synuclein family analyzed in this study were predicted to be highly disordered proteins, indicating that their intrinsically disordered nature represents an evolutionary conserved and therefore functionally important feature. A detailed functional disorder analysis of the proteins in the interactomes of the human synuclein family members utilizing a set of commonly used disorder analysis tools showed that the human α-synuclein interactome has relatively higher levels of intrinsic disorder as compared with the interactomes of human β- and γ- synucleins and revealed that, relative to the β- and γ-synuclein interactomes, α-synuclein interactors are involved in a much broader spectrum of highly diversified functional pathways. Although proteins interacting with three human synucleins were characterized by highly diversified functionalities, this analysis also revealed that the interactors of three human synucleins were involved in three common functional pathways, such as the synaptic vesicle cycle, serotonergic synapse, and retrograde endocannabinoid signaling. Taken together, these observations highlight the critical importance of the intrinsic disorder of human synucleins and their interactors in various neuronal processes.
在这项工作中，我们探索了三种突触核蛋白家族成员——α-、β-和γ-突触核蛋白——的固有无序状态，并表明尽管这三种人类突触核蛋白都高度无序，但最高水平的无序存在于γ-突触核蛋白中。我们对人类突触核蛋白家族成员的氨基酸序列和建模的 3D 结构的特点进行了分析，结果表明，与帕金森病的早发性相关的病理性突变 A30P、E46K、H50Q、A53T 和 A53E 导致人类α-突触核蛋白的局部无序倾向略有增加。对来自不同进化距离物种的突触核蛋白进行基于序列的比较分析，并使用一组常用的生物信息学工具评估其固有无序程度，结果表明，在所分析的突触核蛋白家族的所有成员中，无论其起源如何，都预测为高度无序的蛋白质，这表明它们的固有无序性质代表了一种进化上保守的、因此具有重要功能的特征。利用一组常用的无序分析工具，对人类突触核蛋白家族成员的相互作用组中的蛋白质进行详细的功能无序分析，结果表明，与人类β-和γ-突触核蛋白的相互作用组相比，人类α-突触核蛋白的相互作用组具有相对较高的固有无序程度，并表明与β-和γ-突触核蛋白相互作用组相比，α-突触核蛋白的相互作用物参与了更广泛的高度多样化的功能途径。尽管与三种人类突触核蛋白相互作用的蛋白质具有高度多样化的功能，但这一分析也表明，三种人类突触核蛋白的相互作用物参与了三个共同的功能途径，如突触小泡循环、5-羟色胺能突触和逆行内源性大麻素信号。综上所述，这些观察结果突出了人类突触核蛋白及其相互作用物在各种神经元过程中的固有无序的重要性。
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