Characterization of a possible amyloidogenic precursor in glutamine-repeat neurodegenerative diseases
Characterization of a possible amyloidogenic precursor in glutamine-repeat neurodegenerative diseases
复制标题
DOI：
10.1073/pnas.0502068102
复制
发表时间：
2005-09-20
影响因子：
11.1
通讯作者：
Daggett, V
中科院分区：
文献类型：
--
作者：
Armen, RS;Bernard, BM;Daggett, V
一些神经退行性疾病与谷氨酰胺残基的扩大重复有关，这会导致淀粉样纤维的形成和神经元死亡。重复序列的长度与亨廷顿氏病的发病时间相关，因此，健康个体具有<；38残基，而>；38重复序列的个体表现出症状。由于在实验上很难获得聚(L)-谷氨酰胺(PolyQ)在水溶液中的原子分辨结构信息，我们进行了分子动力学模拟来研究这种均聚物的构象行为。在对20-、40-和80-聚多Q的模拟中，我们观察到了“α-延伸链”构象的形成，其特征是α(L)和α(R)构象中的残基交替形成一张纸。从无序无规卷曲构象到α-扩链构象的结构转变表现出适度的长度和温度依赖关系，这与实验观察到的聚集依赖于长度和温度是一致的。我们认为多聚Q中纤维的形成可能通过a-折叠结构发生，这是由Pauling和Corey[Pauling，L.&Corey，R.B.(1951)Proc]提出的。娜塔莉。阿卡德。SCI。美国37,251-256]。此外，我们提出了一个原子分辨模型，说明抑制肽QBP1(多Q结合肽1)如何以α-延伸链构象与多聚Q结合，以抑制纤维的形成。
Several neurodegenerative diseases are linked to expanded repeats of glutamine residues, which lead to the formation of amyloid fibrils and neuronal death. The length of the repeats correlates with the onset of Huntington's disease, such that healthy individuals have < 38 residues and individuals with > 38 repeats exhibit symptoms. Because it is difficult to obtain atomic-resolution structural information for poly((L)-glutamine) (polyQ) in aqueous solution experimentally, we performed molecular dynamics simulations to investigate the conformational behavior of this homopolymer. In simulations of 20-, 40-, and 80-mer polyQ, we observed the formation of the "alpha-extended chain" conformation, which is characterized by alternating residues in the alpha(L) and alpha(R) conformations to yield a sheet. The structural transition from disordered random-coil conformations to the a-extended chain conformation exhibits modest length and temperature dependence, in agreement with the experimental observation that aggregation depends on length and temperature. We propose that fibril formation in polyQ may occur through an a-sheet structure, which was proposed by Pauling and Corey [Pauling, L. & Corey, R. B. (1951) Proc. Natl. Acad. Sci. USA 37, 251-256]. Also, we propose an atomic-resolution model of how the inhibitory peptide QBP1 (polyQ-binding peptide 1) may bind to polyQ in an alpha-extended chain conformation to inhibit fibril formation.