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The PKD domain distinguishes the trafficking and amyloidogenic properties of the pigment cell protein PMEL and its homologue GPNMB

Authors

  • Alexander C. Theos,

    1. Departments of Pathology & Laboratory Medicine and Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    2. Department of Human Science, School of Nursing and Health Studies, Georgetown University, Washington, DC, USA
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    • These two authors contributed equally to this manuscript.
  • Brenda Watt,

    1. Departments of Pathology & Laboratory Medicine and Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    2. Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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    • These two authors contributed equally to this manuscript.
  • Dawn C. Harper,

    1. Departments of Pathology & Laboratory Medicine and Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Karolina J. Janczura,

    1. Department of Human Science, School of Nursing and Health Studies, Georgetown University, Washington, DC, USA
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  • Sarah C. Theos,

    1. Departments of Pathology & Laboratory Medicine and Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Kathryn E. Herman,

    1. Departments of Pathology & Laboratory Medicine and Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Michael S. Marks

    Corresponding author
    1. Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    • Departments of Pathology & Laboratory Medicine and Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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CORRESPONDENCE M. S. Marks, e-mail: marksm@mail.med.upenn.edu

Summary

Proteolytic fragments of the pigment cell-specific glycoprotein, PMEL, form the amyloid fibrillar matrix underlying melanins in melanosomes. The fibrils form within multivesicular endosomes to which PMEL is selectively sorted and that serve as melanosome precursors. GPNMB is a tissue-restricted glycoprotein with substantial sequence homology to PMEL, but no known function, and was proposed to localize to non-fibrillar domains of distinct melanosome subcompartments in melanocytes. Here we confirm that GPNMB localizes to compartments distinct from the PMEL-containing multivesicular premelanosomes or late endosomes in melanocytes and HeLa cells, respectively, and is largely absent from fibrils. Using domain swapping, the unique PMEL localization is ascribed to its polycystic kidney disease (PKD) domain, whereas the homologous PKD domain of GPNMB lacks apparent sorting function. The difference likely reflects extensive modification of the GPNMB PKD domain by N-glycosylation, nullifying its sorting function. These results reveal the molecular basis for the distinct trafficking and morphogenetic properties of PMEL and GPNMB and support a deterministic function of the PMEL PKD domain in both protein sorting and amyloidogenesis.

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