Identification of a RAB32-LRMDA-Commander membrane trafficking complex reveals the molecular mechanism of human oculocutaneous albinism type 7
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.
Authors
- Cecilia de Heus (ORCID: https://orcid.org/0000-0001-8618-8451)
- Rebeka Butkovič (ORCID: https://orcid.org/0000-0002-6911-1265)
- Wyatt Beyers (ORCID: https://orcid.org/0000-0001-9095-2715)
- Philip A. Lewis (ORCID: https://orcid.org/0000-0002-2868-2459)
- Brett M. Collins (ORCID: https://orcid.org/0000-0002-6070-3774)
- Michael D. Healy (ORCID: https://orcid.org/0000-0003-2924-9179)
- Peter J. Cullen (ORCID: https://orcid.org/0000-0002-9070-8349)
- Judith Klumperman (ORCID: https://orcid.org/0000-0003-4835-6228)
- Kerrie E. McNally (ORCID: https://orcid.org/0000-0003-2376-3003)
- Nalan Liv (ORCID: https://orcid.org/0000-0003-2654-9117)
- Kate J. Heesom (ORCID: https://orcid.org/0000-0002-5418-5392)
- Santiago M. Di Pietro (ORCID: https://orcid.org/0000-0002-3372-8757)
- Alexander P. Walker (ORCID: https://orcid.org/0000-0002-9650-382X)
Institutions
- The University of Queensland (AU)
- MRC Laboratory of Molecular Biology (GB)
- Utrecht University (NL)
- University Medical Center Utrecht (NL)
- University of Bristol (GB)
- Colorado State University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-02
- DOI
- https://doi.org/10.1038/s41467-025-63855-8
- Primary Topic
- melanin and skin pigmentation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Wellcome Trust
- University of Bristol
- Lister Institute of Preventive Medicine
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Institutes of Health
- Medical Research Council