Assessing the contribution of heterogeneous distributions of oligomers to aggregation mechanisms of polyglutamine peptides.
Assessing the contribution of heterogeneous distributions of oligomers to aggregation mechanisms of polyglutamine peptides.
复制标题
评估寡聚物的异质分布对聚谷氨酰胺肽聚集机制的贡献。
DOI：
10.1016/j.bpc.2011.04.006
复制
发表时间：
2011-11
影响因子：
3.8
通讯作者：
Pappu, Rohit V.
中科院分区：
文献类型：
--
作者：
Vitalis, Andreas;Pappu, Rohit V.
多聚谷氨酰胺聚集与九种不同疾病的神经变性相关。聚谷氨酰胺长度和肽浓度对聚集动力学的影响先前使用均质成核模型进行了分析，该模型假设沿着自由能曲线G（n）存在单个瓶颈，其中n表示聚谷氨酰胺分子的数量。观察到的稳定的，可溶性的低聚物作为中间体沿着聚集途径是耐火的假设均匀成核。此外，使用均匀成核的特定变体对体外动力学数据的分析导致混淆观察结果，例如临界核尺寸估计的分数和/或负值。在这里，我们表明，均匀成核模型是固有的强大的，是不太可能产生分数值，如果基本的过程是严格均匀的自由能曲线G（n），显示一个尖锐的最大值在n=n*，其中n* 对应于临界核。相反，一个模型，其中包括不同的大小和不同的潜力，以支持周转成原纤维的低聚物产生的估计分数和/或负核大小时，动力学数据进行分析，使用一个均匀的过程的假设。该模型提供了一种途径，以调和独立的观察结果的非均匀分布的低聚物和其他非纤维状聚集体的聚集动力学分析使用的假设，一个均匀的成核模型。在新模型中，原纤维组装的机制由两种类型的低聚物的相对稳定性决定，原纤维感受态和原纤维不感受态低聚物、最小原纤维感受态低聚物的尺寸和不同低聚物内的构象转化率。
Polyglutamine aggregation is associated with neurodegeneration in nine different disorders. The effects of polyglutamine length and peptide concentration on the kinetics of aggregation were previously analyzed using a homogeneous nucleation model that assumes the presence of a single bottleneck along the free energy profile G(n), where n denotes the number of polyglutamine molecules. The observation of stable, soluble oligomers as intermediates along aggregation pathways is refractory to the assumptions of homogeneous nucleation. Furthermore, the analysis of in vitro kinetic data using a specific variant of homogeneous nucleation leads to confounding observations such as fractional and / or negative values for estimates of the critical nucleus size. Here, we show that the homogeneous nucleation model is inherently robust and is unlikely to yield fractional values if the underlying process is strictly homogeneous with a free energy profile G(n) that displays a sharp maximum at n=n*, where n* corresponds to the critical nucleus. Conversely, a model that includes oligomers of different size and different potentials for supporting turnover into fibrils yields estimates of fractional and / or negative nucleus sizes when the kinetic data are analyzed using the assumption of a homogeneous process. This model provides a route to reconcile independent observations of heterogeneous distributions of oligomers and other non-fibrillar aggregates with results obtained from analysis of aggregation kinetics using the assumption of a homogeneous nucleation model. In the new model, the mechanisms of fibril assembly are governed by the relative stabilities of two types of oligomers viz., fibril-competent and fibril-incompetent oligomers, the size of the smallest fibril competent oligomer, and rates for conformational conversion within different oligomers.
登录
查看更多内容
影响因子：
3.3
作者：
Andrews, Jennifer M.;Roberts, Christopher J.
通讯作者：
Roberts, Christopher J.
影响因子：
3.4
作者：
Darnell, Gregory D.;Derryberry, JohnMark;Meredith, Stephen C.
通讯作者：
Meredith, Stephen C.
影响因子：
4.8
作者：
Bader, Reto;Seeliger, Markus A.;Itzhaki, Laura S.
通讯作者：
Itzhaki, Laura S.
影响因子：
4.7
作者：
Berke, SJS;Schmied, FAF;Paulson, HL
通讯作者：
Paulson, HL
DOI：
10.1073/pnas.041566798
发表时间：
2001-02-13
影响因子：
11.1
作者：
Holbert, S;Denghien, I;Néri, C
通讯作者：
Néri, C