9lip
The cryo-EM structure of the native PMEL fibril lamella
Structural highlights
FunctionPMEL_HUMAN Plays a central role in the biogenesis of melanosomes. Involved in the maturation of melanosomes from stage I to II. The transition from stage I melanosomes to stage II melanosomes involves an elongation of the vesicle, and the appearance within of distinct fibrillar structures. Release of the soluble form, ME20-S, could protect tumor cells from antibody mediated immunity.[1] Publication Abstract from PubMedMelanin synthesis within melanosomes critically depends on the fibrillar architecture formed by the pigment cell-specific protein PMEL. Although PMEL fibrils have historically been classified as functional amyloids, their native supramolecular organization in situ and detailed molecular architecture have remained unresolved. In this study, we combine in situ cryo-electron tomography (cryo-ET) and cryo-electron microscopy (cryo-EM) to elucidate the native structural organization of PMEL fibrils within human melanosomes from both patient melanoma tissues and melanocyte cell lines. We demonstrate that PMEL does not form conventional isolated amyloid fibrils, but rather assembles into highly organized lamellar sheets consisting of laterally aligned fibrils interconnected by flexible linker regions. Cryo-EM structures reveal a distinctive butterfly-shaped fibril unit composed of multiple structured domains, including both the proteolytically cleaved Malpha and Mbeta fragments of PMEL, which assemble into a amyloid-like beta-sheet arrangement. Notably, we identify intrinsically disordered regions critical for lamellar assembly and curvature and verify key glycosylation modifications in the structure. This architecture distinguishes PMEL fibrils from canonical amyloids and elucidates the molecular basis underlying melanosome integrity and pigmentation. Moreover, our work provides molecular insights relevant for pigmentation disorders and PMEL-associated diseases, including melanoma. Atomic structure and in situ visualization of native PMEL lamellae in melanosomes.,Ma B, Yao Y, Dong H, Yang L, Li D, Zhao Q, Sun B, Chen Y, Liu C, Li D Nat Commun. 2025 Nov 21;16(1):10300. doi: 10.1038/s41467-025-65221-0. PMID:41271718[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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