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首页> 外文期刊>Biochimica et biophysica acta. Biomembranes >Membrane-induced initial structure of alpha-synuclein control its amyloidogenesis on model membranes
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Membrane-induced initial structure of alpha-synuclein control its amyloidogenesis on model membranes

机译：膜诱导的α-突触核蛋白的初始结构对其模型膜的淀粉样蛋白产生

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摘要

Amyloid fibrillation causes serious neurodegenerative diseases and amyloidosis; however, the detailed mechanisms by which the structural states of precursor proteins in a lipid membrane-associated environment contribute to amyloidogenesis still remains to be elucidated. We examined the relationship between structural states of intrinsically-disordered wild-type and mutant alpha-synuclein (alpha SN) and amyloidogenesis on two-types of model membranes. Highly-unstructured wild-type aSN (alpha SNWT) and a C-terminally-truncated mutant lacking negative charges (alpha SN103) formed amyloid fibrils on both types of membranes, the model membrane mimicking presynaptic vesicles (Mimic membrane) and the model membrane of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC membrane). Unstructured alpha SNWT and alpha SN103 both bound to Mimic membranes in a helical conformation with similar binding affinity. Promotion and then inhibition of amyloidogenesis of alpha SNWT were observed as the concentration of Mimic lipids increased. We explain this by the two-state binding model: at lower lipid concentrations, binding of alpha SNWT to membranes enhances amyloidogenicity by increasing the local concentration of membrane-bound alpha SN and so promoting amyloid nucleation; at higher lipid concentrations, membrane-bound aSN is actually in a sense diluted by increasing the number of model membranes, which blocks amyloid fibrillation due to an insufficient bound population for productive nucleation. Meanwhile, alpha SN103 formed amyloid fibrils over the whole concentration of Mimic lipids used here without inhibition, revealing the importance of helical structures for binding affinity and negatively charged unstructured C-terminal region for modulating amyloidogenesis. We propose that membrane binding-induced initial conformations of alpha SN, its overall charge states, and the population of membrane-bound alpha SN are key determinants of amyloidogenesis on membranes.
机译：淀粉样纤维颤动导致严重的神经退行性疾病和淀粉样变;然而，详细的机制，通过该脂质膜相关环境的前体蛋白的结构状态有助于淀粉状蛋白仍然有待阐明。我们研究了两种类型的模型膜的内在障碍性的野生型和突变型α-突触核蛋白（阿尔法SN）和淀粉状蛋白生成的结构状态之间的关系。高度非结构化野生型ASN（阿尔法南水北调）和一个C-末端截短突变体缺乏负电荷（阿尔法SN103）在两个类型的膜的形成淀粉样蛋白原纤维，模型膜模仿突触前小泡（模拟物膜）和模型膜1,2-二油酰基-sn-甘油-3-磷酸胆碱（DOPC膜）。非结构化阿尔法南水北调和αSN103都在具有类似结合亲和力的螺旋构象结合到模仿膜。观察到的α-南水北调的淀粉样蛋白促进和抑制然后物模拟脂质的浓度增加。我们通过两状态结合模型解释这一点：在较低的脂质浓度，通过增加膜结合的α-SN的局部浓度和因此促进淀粉状蛋白核化的α南水北调到膜增强amyloidogenicity的结合;在更高的脂质浓度，膜结合的ASN实际上是通过增加膜模型，其阻断淀粉样蛋白纤维性颤动的数量稀释感由于界人口不足以生产成核。另一方面，α-SN103形成淀粉样蛋白原纤维在这里使用，而不抑制模仿脂质的整体浓度，揭示用于结合亲和力螺旋结构的重要性和用于调节淀粉状蛋白生成带负电荷的非结构化C末端区域。我们建议膜结合诱导阿尔法SN，它的整体电荷状态的初始构象，和膜结合的αSN的人口都在膜淀粉样蛋白的关键因素。

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