Mossuto Maria F, Dhulesia Anne, Devlin Glyn, Frare Erica, Kumita Janet R, de Laureto Patrizia Polverino, Dumoulin Mireille, Fontana Angelo, Dobson Christopher M, Salvatella Xavier
Institute for Research in Biomedicine, Barcelona, Spain.
J Mol Biol. 2010 Oct 8;402(5):783-96. doi: 10.1016/j.jmb.2010.07.005. Epub 2010 Jul 17.
Identifying the cause of the cytotoxicity of species populated during amyloid formation is crucial to understand the molecular basis of protein deposition diseases. We have examined different types of aggregates formed by lysozyme, a protein found as fibrillar deposits in patients with familial systemic amyloidosis, by infrared spectroscopy, transmission electron microscopy, and depolymerization experiments, and analyzed how they affect cell viability. We have characterized two types of human lysozyme amyloid structures formed in vitro that differ in morphology, molecular structure, stability, and size of the cross-β core. Of particular interest is that the fibrils with a smaller core generate a significant cytotoxic effect. These findings indicate that protein aggregation can give rise to species with different degree of cytotoxicity due to intrinsic differences in their physicochemical properties.
确定淀粉样蛋白形成过程中聚集的物种的细胞毒性原因对于理解蛋白质沉积疾病的分子基础至关重要。我们通过红外光谱、透射电子显微镜和解聚实验研究了溶菌酶形成的不同类型聚集体，溶菌酶是在家族性系统性淀粉样变性患者中发现的呈纤维状沉积物的一种蛋白质，并分析了它们如何影响细胞活力。我们表征了体外形成的两种人类溶菌酶淀粉样结构，它们在形态、分子结构、稳定性和交叉β核心大小方面存在差异。特别有趣的是，具有较小核心的原纤维产生了显著的细胞毒性作用。这些发现表明，由于其物理化学性质的内在差异，蛋白质聚集可产生具有不同细胞毒性程度的物种。
