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

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, Brett M. Collins and Peter J. Cullen ()
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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

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63855-8

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