Structure and Function of Alpha-Synuclein

描述(由申请人提供)：α-突触核蛋白(AS)的聚集在帕金森病(PD)的发病机制中扮演着重要但仍鲜为人知的角色。AS的正常功能尚不清楚，但该蛋白结合到磷脂膜上，被认为调节突触囊泡池的大小、囊泡的循环、神经递质的运输和释放以及突触的可塑性。自从AS和PD之间的联系被发现以来，人们一直对识别影响蛋白质致病或正常作用的相互作用伙伴产生了极大的兴趣。在过去的几年里，越来越多的蛋白质、聚合物和小分子被报道与AS结合并改变其聚集动力学和/或其脂质相关功能。其中包括突触核蛋白家族的另外两个成员，B-突触核蛋白(BS)和Y-突触核蛋白(YS)。共价修饰也影响AS的聚集和功能。然而，这些不同的结合相互作用和修饰影响行为的机制还不是很清楚。我们已经证明，游离AS中的残基结构可能在该蛋白形成淀粉样原纤维之前的分子间相互作用中发挥重要作用。我们假设，在共价修饰或伴侣相互作用时，AS经历构象变化，从而对蛋白质的聚集或正常功能产生影响。因此，我们建议在高分辨率下表征AS中发生的结构变化作为其修饰的结果以及它与不同伙伴的相互作用，最初的重点是(BS、Y、组蛋白、HSP70、PLD2、铜和其他金属和多阳离子)。我们还建议详细阐明(BS和Y)在自由和脂质结合状态下的结构，以阐明为什么AS表现出与这些近亲不同的自组装行为。最后，我们计划通过合作将合理设计的突变体引入AS毒性和功能的酵母和苍蝇模型中来测试我们关于结构变化在AS中的作用的结论。建议的研究集中于提高我们对帕金森病潜在的分子机制的理解，并可能为开发新的帕金森病疗法提供策略建议。这一结果可能对理解和治疗其他淀粉样蛋白疾病具有更广泛的意义，包括阿尔茨海默病和普里恩疾病。

DESCRIPTION (provided by applicant): Aggregation of a-synuclein (aS) plays an important but still poorly understood role in the pathogenesis of Parkinson's disease (PD). The normal function of aS remains unknown, but the protein binds to phospholipid membranes and is believed to regulate synaptic vesicle pool size, vesicle recycling, neurotransmitter transport and release, and synaptic plasticity. Since the discovery of the link between aS and PD, there has been great interest in identifying aS interaction partners that influence either the pathogenic or normal roles of the protein. In the past few years, a growing number of proteins, polymers, and small molecules have been reported to bind to aS and alter its aggregation kinetics and/or its lipid-associated functions. Among these are two other members of the synuclein family, B-synuclein (BS) and y-synuclein (yS). Covalent modifications also affect aS aggregation and function. However, the mechanisms by which these various binding interactions and modifications influence aS behavior are not well understood. We have shown that residual structure in free aS may play an important role in mediating the intermolecular interactions that precede amyloid fibril formation by this protein. We hypothesize that upon covalent modification or partner interactions, aS undergoes conformational changes that underlie the consequent effects on the aggregation or normal functions of the protein. We therefore propose to characterize, at high resolution, the structural changes that occur in aS as a function of its modifications and its interactions with different partners, with an initial focus on (BS, yS, histones, HSP70, PLD2, copper and other metals and polycations. We also propose to elucidate in detail the structure of (BS and yS in their free and lipid-bound states to clarify why aS exhibits different self-assembly behavior from these close relatives. Finally, we plan to test our conclusions regarding the role of structural changes in aS by introducing rationally designed mutants, collaboratively, into yeast and fly models of aS toxicity and function. The proposed studies are focused on improving our understanding of the molecular mechanisms underlying PD and may suggest strategies for developing new PD therapeutics. The results may have broader implications for understanding and treating other amyloid diseases, including Alzheimer's disease and the prion diseases.