He Xianglan, Giurleo Jason T, Talaga David S
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
J Mol Biol. 2010 Jan 8;395(1):134-54. doi: 10.1016/j.jmb.2009.10.019. Epub 2009 Oct 27.
We combine atomic-force-microscopy particle-size-distribution measurements with earlier measurements on 1-anilino-8-naphthalene sulfonate, thioflavin T, and dynamic light scattering to develop a quantitative kinetic model for the aggregation of beta-lactoglobulin into amyloid. We directly compare our simulations to the population distributions provided by dynamic light scattering and atomic force microscopy. We combine species in the simulation according to structural type for comparison with fluorescence fingerprint results. The kinetic model of amyloidogenesis leads to an aggregation free-energy landscape. We define the roles of and propose a classification scheme for different oligomeric species based on their location in the aggregation free-energy landscape. We relate the different types of oligomers to the amyloid cascade hypothesis and the toxic oligomer hypothesis for amyloid-related diseases. We discuss existing kinetic mechanisms in terms of the different types of oligomers. We provide a possible resolution to the toxic oligomer-amyloid coincidence.
我们将原子力显微镜颗粒尺寸分布测量结果与早期对1-苯胺基-8-萘磺酸盐、硫黄素T的测量以及动态光散射相结合，以建立β-乳球蛋白聚集成淀粉样蛋白的定量动力学模型。我们将模拟结果与动态光散射和原子力显微镜提供的群体分布直接进行比较。在模拟中，我们根据结构类型对物种进行组合，以便与荧光指纹结果进行比较。淀粉样蛋白生成的动力学模型导致了一个聚集自由能景观。我们定义了不同寡聚体物种的作用，并根据它们在聚集自由能景观中的位置提出了一种分类方案。我们将不同类型的寡聚体与淀粉样蛋白相关疾病的淀粉样蛋白级联假说和有毒寡聚体假说联系起来。我们根据不同类型的寡聚体讨论了现有的动力学机制。我们为有毒寡聚体与淀粉样蛋白的巧合提供了一种可能的解决方案。
