{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPMEL (also known as Pmel17 or gp100) is a melanocyte‐specific glycoprotein essential for the biogenesis of melanosomes—the organelles where melanin is synthesized and stored. Synthesized as an integral membrane protein, PMEL undergoes a series of tightly regulated posttranslational modifications and sorting events. In a post‐Golgi compartment, it is cleaved into disulfide‐linked subunits and routed into the intralumenal vesicles of multivesicular bodies (precursors of melanosomes), in a process mediated by luminal determinants and independent of classical cytoplasmic signals. Moreover, transcriptional regulation by factors such as MITF ensures high‐level expression in pigment cells, and its proper sorting may involve adaptor complex (AP) components that recognize distinct domains of PMEL."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA hallmark of PMEL function is its capacity to form functional amyloid fibrils that serve as an internal scaffold for safe melanin deposition. This fibrillogenic conversion is initiated by specific proteolytic cleavages including an early “S2‐like” juxtamembrane cut and further processing events—in some instances requiring enzymes such as furin‐like proprotein convertases and even BACE2—that release luminal fragments competent for self‐assembly. The repeat (RPT) domain, which forms amyloid only under the mildly acidic conditions typical of melanosomes, together with contributions from a polycystic kidney disease–like (PKD) domain and an N‐terminal region, constitute the structural core driving fibril nucleation and growth. Notably, alternative splicing and glycosylation events further modulate the amyloidogenic potential of PMEL, and ectodomain shedding can generate secreted species."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "13"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in fibril formation and melanosome maturation, PMEL’s processing and trafficking have broader functional implications. Its fragments not only create a template on which melanins polymerize but also contribute indirectly to immune recognition of melanoma cells, as peptides derived from PMEL can be presented to T lymphocytes. Disruptions in PMEL processing—for example, due to mutations that truncate the cytoplasmic tail or alter its transmembrane oligomerization—lead to aberrant fibril formation and pigment dilution, as exemplified by the silver and dominant white phenotypes in animals. In addition, interactions with other melanocyte-specific proteins (such as MART-1) and the influence of lipid environments further fine-tune its fibrillogenic behavior, making PMEL a key determinant of both melanosome structure and pigmentation homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "J F Berson, D C Harper, D Tenza, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200302072"}], "href": "https://doi.org/10.1083/jcb.200302072"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12732614"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12732614"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jinyan Du, Arlo J Miller, Hans R Widlund, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0002-9440(10)63657-7"}], "href": "https://doi.org/10.1016/S0002-9440(10"}, {"type": "t", "text": "63657-7) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12819038"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12819038"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Julio C Valencia, Hidenori Watabe, An Chi, et al. 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