在这项工作中,我们探索了突触核蛋白家族的三个成员的内在紊乱状态-α-,β-,和γ-突触核蛋白-并表明尽管所有三种人类突触核蛋白都是高度无序的,在γ-突触核蛋白中观察到最高水平的疾病。我们对人类突触核蛋白家族成员的氨基酸序列和建模3D结构的特殊性的分析揭示了病理突变A30P,E46K,H50Q,A53T,与帕金森病早期发病相关的A53E导致人类α-突触核蛋白局部紊乱倾向增加。对来自各种进化遥远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内在紊乱水平,不管他们的起源,在这项研究中分析的突触核蛋白家族的所有成员都被预测为高度无序的蛋白质,表明它们的内在无序性质代表了进化保守的特征,因此具有重要的功能。利用一组常用的疾病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了详细的功能紊乱分析,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-突触核蛋白相互作用组具有相对较高的内在紊乱水平,相对于β-和γ-突触核蛋白相互作用,α-突触核蛋白相互作用物涉及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,这项分析还揭示了三种人类突触核蛋白的相互作用者参与了三种常见的功能途径,比如突触小泡周期,血清素能突触,和逆行内源性大麻素信号。一起来看,这些观察结果强调了人类突触核蛋白的内在紊乱及其在各种神经元过程中的相互作用者的重要性。
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.