β-hairpin-mediated formation of structurally distinct multimers of neurotoxic prion peptides.
β-hairpin-mediated formation of structurally distinct multimers of neurotoxic prion peptides.
复制标题
DOI：
10.1371/journal.pone.0087354
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Gill AC
中科院分区：
文献类型：
--
作者：
Gill AC
蛋白质错误折叠疾病与特定蛋白质的构象变化相关，导致潜在神经毒性淀粉样原纤维的形成。在朊病毒疾病的发病过程中，朊病毒蛋白错误折叠成富含β折叠的蛋白酶抗性同种型。朊病毒蛋白内的一个关键疏水结构域，包括残基109-122，概括了完整蛋白的许多性质，如螺旋到折叠结构的转变，原纤维的形成和错误折叠同种型的细胞毒性。使用全原子分子模拟，证明了单体109-122肽具有α-螺旋构象的偏好，但是该肽也可以形成β-发夹结构，这是由肽的特定甘氨酸残基周围的转弯引起的。改变109-122肽（A117 V，与家族性朊病毒病相关）内的单个氨基酸增加了β-发夹形成的流行率，并且这些观察结果在包含残基106-126的较长肽中重复。多分子聚集模拟产生由构象不同的单体单元组成的肽分子的不同组装体。与低聚物一致的小分子组装体包含β-发夹状构象的肽单体，并且在许多模拟中似乎仅短暂存在。相反，较大的组装体由主要反向平行β折叠的延伸肽组成，并且相对于模拟的长度是稳定的。这些较大的组装体与淀粉样蛋白原纤维一致，显示出交叉β结构，并且可以通过预先存在的低聚物内的单体单元的延伸形成。在一些模拟中，含有β-发夹和线性肽两者的组装体是明显的。因此，在这项工作中，寡聚体在原纤维形成的途径上，并且对β-发夹结构的偏好应该增强寡聚体形成，同时抑制成熟为原纤维。这些模拟为朊病毒蛋白的寡聚体和原纤维的形成提供了一个重要的新的原子水平模型，并表明β-发夹结构的稳定性可能通过改变寡聚体和原纤维蛋白组装体之间的平衡来增强细胞毒性。
Protein misfolding disorders are associated with conformational changes in specific proteins, leading to the formation of potentially neurotoxic amyloid fibrils. During pathogenesis of prion disease, the prion protein misfolds into β-sheet rich, protease-resistant isoforms. A key, hydrophobic domain within the prion protein, comprising residues 109–122, recapitulates many properties of the full protein, such as helix-to-sheet structural transition, formation of fibrils and cytotoxicity of the misfolded isoform. Using all-atom, molecular simulations, it is demonstrated that the monomeric 109–122 peptide has a preference for α-helical conformations, but that this peptide can also form β-hairpin structures resulting from turns around specific glycine residues of the peptide. Altering a single amino acid within the 109–122 peptide (A117V, associated with familial prion disease) increases the prevalence of β-hairpin formation and these observations are replicated in a longer peptide, comprising residues 106–126. Multi-molecule simulations of aggregation yield different assemblies of peptide molecules composed of conformationally-distinct monomer units. Small molecular assemblies, consistent with oligomers, comprise peptide monomers in a β-hairpin-like conformation and in many simulations appear to exist only transiently. Conversely, larger assemblies are comprised of extended peptides in predominately antiparallel β-sheets and are stable relative to the length of the simulations. These larger assemblies are consistent with amyloid fibrils, show cross-β structure and can form through elongation of monomer units within pre-existing oligomers. In some simulations, assemblies containing both β-hairpin and linear peptides are evident. Thus, in this work oligomers are on pathway to fibril formation and a preference for β-hairpin structure should enhance oligomer formation whilst inhibiting maturation into fibrils. These simulations provide an important new atomic-level model for the formation of oligomers and fibrils of the prion protein and suggest that stabilization of β-hairpin structure may enhance cellular toxicity by altering the balance between oligomeric and fibrillar protein assemblies.
登录
查看更多内容
影响因子：
34.7
作者：
Frost, Bess;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
DOI：
10.1080/07391102.2011.10507403
发表时间：
2011-12-01
影响因子：
4.4
作者：
Cao, Zanxia;Liu, Lei;Wang, Jihua
通讯作者：
Wang, Jihua
影响因子：
3.4
作者：
Chiesa, R;Angeretti, N;Forloni, G
通讯作者：
Forloni, G
DOI：
10.1016/0006-291x(89)92317-6
发表时间：
1989-09-15
影响因子：
3.1
作者：
DOHURA, K;TATEISHI, J;SAKAKI, Y
通讯作者：
SAKAKI, Y
DOI：
10.1073/pnas.97.2.571
发表时间：
2000-01-18
影响因子：
11.1
作者：
Conway, KA;Lee, SJ;Lansbury, PT
通讯作者：
Lansbury, PT