Commanding the Commander:structure of a key protein machinery in endosomal trafficking

In a recent study published in Cell1 and two bioRxiv pre-prints,2,3 three studies investigate the structure of the endosomal Commander complex through a combination of X-ray crystal-lography,cryogenic-electron microscopy(Cryo-EM),Alphafold predictions and extensive site-directed mutagenesis(Fig.1a),which sheds lights on the molecular characteristics of this evolutionarily-conserved protein machinery,and enables the mapping of mutations causing X-linked intellectual disability(XILD)and Ritscher-Schinzel syndrome(RSS).When proteins enter the endosomal network,they are either transported to lysosome for degradation,or recycled to the plasma membrane or the trans-Golgi network for reuse.Multiple protein machineries are essential for the process,including Retromer,Commander,and several members of the sorting nexin(SNX)family.Commander genes are highly conserved in metazoa and can be found in almost all tissues and cells.

All ways lead to Rome: assembly of retromer on membranes with different sorting nexins

In a recent paper published in Science Advances,Leneva et al.1 present cryo-electron tomography structures of assembling metazoan and fungal core retromer complexes(VPS29/VPS35/VPS26)on membranes enriched in Фx(L/M/V)motif(where Ф is a bulky aromatic residue)-containing cargo and sorting nexin 3(SNX3).The structures suggest that retromer forms a conserved arch-like scaffold that can incorporate different types of membrane adaptors and cargoes.More surprisingly,the SNX3-reotrmer complex is sufficient to induce membrane curvature and tabulation,in the absence of classical membrane curvature drivers,such as bin/amphiphysin/rvs-domain-containing sorting nexin protein(SNX-BARs).