Cryo-EM of wild-type and mutant PMEL amyloid cores reveals structural mechanism of pigment dispersion syndrome

Haruaki Yanagisawa, Harumi Arai, Tony Wang, Hideyuki Miyazawa, Masahide Kikkawa and Toshiyuki Oda ()
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Haruaki Yanagisawa: the University of Tokyo
Harumi Arai: University of Yamanashi
Tony Wang: the University of Tokyo
Hideyuki Miyazawa: University of Yamanashi
Masahide Kikkawa: the University of Tokyo
Toshiyuki Oda: University of Yamanashi

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61233-y

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