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Identification of a RAB32-LRMDA-Commander membrane trafficking complex reveals the molecular mechanism of human oculocutaneous albinism type 7

Author

Listed:
  • Rebeka Butkovič

    (University of Bristol)

  • Michael D. Healy

    (The University of Queensland)

  • Cecilia de Heus

    (Utrecht University)

  • Alexander P. Walker

    (University of Bristol)

  • Wyatt Beyers

    (Fort Collins)

  • Kerrie E. McNally

    (MRC Laboratory of Molecular Biology)

  • Philip A. Lewis

    (University of Bristol)

  • Kate J. Heesom

    (University of Bristol)

  • Nalan Liv

    (Utrecht University)

  • Judith Klumperman

    (Utrecht University)

  • Santiago Di Pietro

    (Fort Collins)

  • Brett M. Collins

    (The University of Queensland)

  • Peter J. Cullen

    (University of Bristol)

Abstract

The endosomal Commander assembly associates with the sorting nexin-17 (SNX17) cargo adaptor to regulate cell surface recycling of internalised integral proteins including integrins and lipoprotein receptors. Here, we identify leucine rich melanocyte differentiation associated (LRMDA) as a Commander binding protein. We reveal that LRMDA and SNX17 share a common mechanism of Commander association, and that LRMDA simultaneously associates with Commander and active RAB32, establishing distinct RAB32-LRMDA-Commander and SNX17-Commander assemblies. Functional analysis in melanocytes reveals distinct roles for RAB32-LRMDA-Commander and SNX17-Commander in melanosome biogenesis. We reveal how LRMDA mutations, causative for oculocutaneous albinism type 7, a hypopigmentation disorder accompanied by poor visual acuity, uncouple RAB32 and Commander binding thereby establishing the mechanistic basis of this disease. Our discovery of this alternative Commander assembly highlights the plasticity of Commander function in human pigmentation and extends the Commander function beyond the SNX17-mediated regulation of cell surface proteome.

Suggested Citation

  • Rebeka Butkovič & Michael D. Healy & Cecilia de Heus & Alexander P. Walker & Wyatt Beyers & Kerrie E. McNally & Philip A. Lewis & Kate J. Heesom & Nalan Liv & Judith Klumperman & Santiago Di Pietro & , 2025. "Identification of a RAB32-LRMDA-Commander membrane trafficking complex reveals the molecular mechanism of human oculocutaneous albinism type 7," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63855-8
    DOI: 10.1038/s41467-025-63855-8
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