Premelanosome amyloid-like fibrils are composed of only Golgi-processed forms of Pmel17 that have been proteolytically processed in Endosomes

被引:67
作者
Harper, Dawn C. [1 ]
Theos, Alexander C. [1 ,2 ]
Herman, Kathryn E. [1 ]
Tenza, Daniele [3 ]
Raposo, Graca [3 ]
Marks, Michael S. [1 ]
机构
[1] Univ Penn, Dept Pathol & Lab Med, Sch Med, Philadelphia, PA 19104 USA
[2] Georgetown Univ, Sch Nursing & Hlth Studies, Dept Human Sci, Washington, DC 20057 USA
[3] Inst Curie, UMR CNRS 144, Sect Rech, F-75248 Paris, France
关键词
D O I
10.1074/jbc.M708007200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Melanin pigments are synthesized within specialized organelles called melanosomes and polymerize on intraluminal fibrils that form within melanosome precursors. The fibrils consist of proteolytic fragments derived from Pmel17, a pigment cell-specific integral membrane protein. The intracellular pathways by which Pmel17 accesses melanosome precursors and the identity of the Pmel17 derivatives within fibrillar melanosomes have been a matter of debate. Weshow here that antibodies that detect Pmel17 within fibrillar melanosomes recognize only the luminal products of proprotein convertase cleavage and not the remaining products linked to the transmembrane domain. Moreover, antibodies to the N and C termini detect only Pmel17 isoforms present in early biosynthetic compartments, which constitute a large fraction of detectable steady state Pmel17 in cell lysates because of slow early biosynthetic transport and rapid consumption by fibril formation. Using an antibody to a luminal epitope that is destroyed upon modification by O-linked oligosaccharides, we show that all post-endoplasmic reticulum Pmel17 isoforms are modified by Golgi-associated oligosaccharide transferases, and that only processed forms contribute to melanosome biogenesis. These data indicate that Pmel17 follows a single biosynthetic route from the endoplasmic reticulum through the Golgi complex and endosomes to melanosomes, and that only fragments encompassing previously described functional luminal determinants are present within the fibrils. These data have important implications for the site and mechanism of fibril formation.
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页码:2307 / 2322
页数:16
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