PDF(Pubmed)
Abstract：
The conversion of a soluble protein into polymeric amyloid structures is a process that is poorly understood. Here, we describe a fully redox-regulated amyloid system in which cysteine oxidation of the tumor suppressor protein p16INK4a leads to rapid amyloid formation. We identify a partially-structured disulfide-bonded dimeric intermediate species that subsequently assembles into fibrils. The stable amyloid structures disassemble when the disulfide bond is reduced. p16INK4a is frequently mutated in cancers and is considered highly vulnerable to single-point mutations. We find that multiple cancer-related mutations show increased amyloid formation propensity whereas mutations stabilizing the fold prevent transition into amyloid. The complex transition into amyloids and their structural stability is therefore strictly governed by redox reactions and a single regulatory disulfide bond.
摘要：
可溶性蛋白质向聚合淀粉样蛋白结构的转化是一个鲜为人知的过程。这里,我们描述了完全氧化还原调节的淀粉样蛋白系统,其中肿瘤抑制蛋白p16INK4a的半胱氨酸氧化导致淀粉样蛋白快速形成.我们确定了部分结构的二硫键二聚体中间体，随后组装成原纤维。当二硫键还原时,稳定的淀粉样蛋白结构分解。p16INK4a在癌症中经常发生突变，被认为极易发生单点突变。我们发现，多种癌症相关突变显示淀粉样蛋白形成倾向增加，而稳定折叠的突变阻止了向淀粉样蛋白的转变。因此，向淀粉样蛋白的复合物转变及其结构稳定性严格受氧化还原反应和单个调节性二硫键的支配。
