Understanding the remodeling of lipid bilayers induced by binding of alpha-Synucl

了解 α-Synucl 结合诱导的脂质双层重塑

• 批准号: 8314956
• 负责人: Anthony Robert Braun
• 金额: $ 2.74万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-29 至 2015-05-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314956
• 关键词: Adopted; Alzheimer' s Disease; Amino Acids; Behavior; Binding; Binding Proteins; Biophysics; Caliber; Cellular Membrane; Charge; Computational Technique; Disease; Future; Goals; Knowledge; Lewy Bodies; Lipid Bilayers; Lipids; Measurement; Measures; Mechanics; Melons; Membrane; Membrane Fusion; Membrane Lipids; Membrane Proteins; Modeling; Molecular; Movement Disorders; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Parkinson Disease; Physiological; Play; Positioning Attribute; Process; Proteins; Research Proposals; Roentgen Rays; Role; Series; Shapes; Stress; Structure; Suggestion; Synaptic Vesicles; Testing; Training; Transgenic Mice; Universities; Vesicle; Work; alpha synuclein; authority; base; density; driving force; insight; mitochondrial membrane; molecular dynamics; monolayer; mouse model; mutant; neurophysiology; research study; simulation; skills; synuclein; tool; trafficking; unilamellar vesicle

DESCRIPTION (provided by applicant): Alpha-Synuclein (alpha-S) is a 140 amino acid, intrinsically disordered protein that adopts an amphipathic alpha-helical structure upon binding the membrane. Alpha-S is the major proteinaceous component of insoluble fibrillar Lewy bodies, a hallmark of Parkinson's disease (PD). The precise roles of both native and pathological forms of alpha-S remain unclear. However, the interaction of alpha-S with cellular membranes is now thought to be critical to its native function, and potentially to its role in PD as well. We propos a series of Low-Angle X-ray Scattering (LAXS) experiments and molecular dynamics (MD) simulations to more fully understand the membrane remodeling effects of native alpha-S. We will be primarily focused on the role of lipid composition and bilayer curvature. In particular, we propose the following two specific aims, each of which will be carried out in parallel: 1) Determine how alpha-S remodels membranes when bound to both monolayer leaflets. 2) Determine how alpha-S remodels membranes when bound to only one leaflet, modeling its physiological action on synaptic vesicles. Each of these aims will test our hypothesis that the intrinsic, natural curvature of alpha-S dictates its capacity to remodel and stabilize membranes, in particular those that are highly curved (like synaptic vesicles). PUBLIC HEALTH RELEVANCE: The membrane protein alpha-synuclein has been implicated as playing a central role in both sporadic and familial forms of Parkinson's disease, the most common neurodegenerative movement disorder. Through developing a biophysical understanding of alpha-synuclein induced membrane remodeling, we will gain insight into the native function of alpha--synuclein, and in turn be well positioned to begin to understand its role in the disease.

描述（由申请人提供）：α-突触核蛋白（α-S）是140个氨基酸，本质上无序的蛋白质，在结合膜时会在结合膜时采用两亲性α-螺旋结构。 Alpha-S是不溶性纤维Lewy Bodies的主要蛋白质成分，帕金森氏病（PD）的标志。 α-S的天然和病理形式的确切作用尚不清楚。然而，α-S与细胞膜的相互作用现在被认为对其天然功能至关重要，并且也可能对其在PD中的作用也至关重要。我们建议一系列低角度X射线散射（LAXS）实验和分子动力学（MD）模拟，以更充分地了解天然α-S的膜重塑作用。我们将主要关注脂质组成和双层曲率的作用。特别是我们 提出以下两个特定目的，每个目标将并行进行：1）确定α-S重塑膜在与两个单层小叶结合时如何重塑膜。 2）确定α-S仅与一个传单结合时如何重塑膜，从而对其对突触囊泡的生理作用进行建模。这些目标中的每一个都将检验我们的假设，即α-S的内在自然曲率决定了其重塑和稳定膜的能力，尤其是那些高度弯曲的膜（如突触囊泡）。 公共卫生相关性：膜蛋白α-突触核蛋白被认为是帕金森氏病（最常见的神经退行性运动障碍）在零星和家族形式的核心作用。通过对α-突触核蛋白诱导的膜重塑的生物物理理解，我们将深入了解α-核蛋白的天然功能，进而可以很好地开始理解其作用 在疾病中。