The multicomponent Retriever-CCC-WASH Complex (the Commander complex; formerly called the PDZ domain-containing SNX31-retromer assembly apparatus). The CCC and WASH complexes appear to function in recruitment to the endosomes. Direct cargo binding may be mediated by the COMMDs (McNally and Cullen 2018).  The structure of the membrane-assembled retromer coat has been determined by cryo-electron tomography (Kovtun et al. 2018) (see family description). These two complexes and their functions have been reviewed (Chen et al. 2019).  Rowlands and Moore 2024 discuss the mechanisms implicated in VPS35-mediated neurodegeneration in Parksenson's Disease, PD,, as well as the interplay between VPS35 and other PD-linked gene products.

The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93.Healy et al. 2023 have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilized by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a 16th subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery (Healy et al. 2023). The vacuolar protein sorting 35 ortholog (VPS35) gene encodes a core component of the retromer complex essential for the endosomal sorting and recycling of transmembrane cargo. Endo-lysosomal pathway deficits are suggested to play a role in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Mutations in VPS35 cause a late-onset, autosomal dominant form of PD, with a single missense mutation (D620N) shown to segregate with disease in PD families (Rowlands and Moore 2024).