Fig. 8: Proposed function for SNX17-Commander and RAB32-LRMDA-Commander in melanosome biology.

A The Commander complex associates with the cargo adaptor SNX17 to mediate the retrieval of cargo from early endosomes to the plasma membrane^1,2,4,16. In this process, SNX17 associates with the endosomal membrane through recognition of phosphatidylinositol-3-monophosphate (PI3P) and, through its FERM domain, binds the N-x-x-[Y/F]-motifs present in the cytosolic domains of cargo. Cargo binding displaces the intramolecular association between the autoinhibitory motif (star symbol) and the cargo-binding pocket of SNX17 FERM domain. The non-autoinhibited cargo-bound SNX17 is then able to associate with the 16-subunit Commander assembly through the interaction between the carboxy-terminal IGDEDL⁴⁷⁰ motif of SNX17 and the Retriever sub-assembly. In a process yet to be fully elucidated, Commander engages the WASH complex to control the dynamic turnover of endosomal actin. Actin branching supports the formation of cargo-loaded tubulo-vesicular carriers that transport cargo to their destination. Here, we propose that SNX17 may additionally protect cargoes, destined for the melanosome compartment, from lysosomal degradation. These cargoes may include regulators of melanosome neutralisation, a process that is necessary for the proper functioning of melanogenic enzymes. For simplicity, other sorting complexes such as ESCPE-I and Retromer, and their cargo, are not shown. B In addition to canonical binding to SNX17, Commander binds to LRMDA in a SNX17-exclusive manner. We propose that in this process, in contrast with PI3P recognition by SNX17, active RAB32^50,77 integrates into organelle membranes through C-terminal geranylgeranylation. Membrane-anchored RAB32 then dynamically recruits LRMDA to melanosome membranes¹⁷. This interaction is stabilised upon LRMDA binding to Commander through a mechanism like SNX17: LRMDA employs a carboxy terminal IRDDQL²²⁶ motif to act as an adaptor between RAB32 and the Retriever sub-assembly of Commander. This direct interaction is necessary to support LRMDA-RAB32-mediated function in melanosome biogenesis, however, future work is required to establish those processes controlled by this assembly and to understand the relationship of this pathway to known melanosome trafficking and biogenesis machinery such as BLOC1-3 and AP-1/3, and to the canonical SNX17-Commander pathway.