Yanagisawa Haruaki, Arai Harumi, Wang Tony, Miyazawa Hideyuki, Kikkawa Masahide, Oda Toshiyuki
Department of Cell Biology and Anatomy, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Department of Anatomy and Structural Biology, Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Nat Commun. 2025 Jul 1;16(1):5411. doi: 10.1038/s41467-025-61233-y.
PMEL amyloids serve as essential scaffolds for melanin deposition in melanosomes, playing a crucial role in pigmentation. Despite their importance, the high-resolution structure of PMEL amyloids has remained unresolved. Using cryo-electron microscopy, we determine near-atomic resolution structures of wild-type PMEL amyloid core, revealing two distinct polymorphic forms with structural features. We further investigate the pathogenic G175S mutation associated with pigment dispersion syndrome (PDS). Structural analysis reveales that G175S introduces an additional hydrogen bond, stabilizing an alternative fibril conformation. In vitro, the G175S mutant exhibits a fourfold increase in polymerization efficiency compared to the wild type. In cells, G175S expression resultes in a twofold increase in intracellular amyloid content and a ~70% increase in extracellular amyloids, without altering melanosome morphology or number. These results indicate that the G175S mutation enhances amyloidogenesis within melanosomes, elevating amyloid load and potentially contributing to PDS pathophysiology. This study provides molecular insights into PMEL amyloid formation, highlighting its structural diversity and dysregulation in pigmentation disorders.
PMEL淀粉样蛋白是黑素体中黑色素沉积的重要支架，在色素沉着中起关键作用。尽管它们很重要，但PMEL淀粉样蛋白的高分辨率结构仍未得到解析。利用冷冻电子显微镜，我们确定了野生型PMEL淀粉样蛋白核心的近原子分辨率结构，揭示了两种具有结构特征的不同多态形式。我们进一步研究了与色素播散综合征（PDS）相关的致病性G175S突变。结构分析表明，G175S引入了一个额外的氢键，稳定了一种替代的原纤维构象。在体外，与野生型相比，G175S突变体的聚合效率提高了四倍。在细胞中，G175S的表达导致细胞内淀粉样蛋白含量增加两倍，细胞外淀粉样蛋白增加约70%，而不改变黑素体的形态或数量。这些结果表明，G175S突变增强了黑素体内的淀粉样蛋白生成，增加了淀粉样蛋白负荷，并可能导致PDS的病理生理过程。这项研究为PMEL淀粉样蛋白的形成提供了分子见解，突出了其在色素沉着障碍中的结构多样性和失调。
