The Commander protein complex and its role in intracellular membrane trafficking

Abstract

Membrane compartmentalisation is a defining feature of all eukaryotic cells and we have evolved sophisticated protein machineries to control the flow of transmembrane molecules and lipids between organelles. One of the most dynamic membrane bound compartments is the early endosome, which controls the sorting of transmembrane cargos as they transit through the secretory and endocytic system. Our lab is deciphering the molecular mechanisms that control this membrane sorting using a combination of structural and cellular biology. ‘Retromer’ is one of the best characterised endosomal transport protein machines, and is mutated in Parkinson’s Disease and recently we and others identified a ‘Retromer‐like’ protein complex named ‘Retriever’. Retriever forms a large macromolecular assembly with other proteins including the so‐called COMMD and CCDC complexes and a member of the sorting nexin protein family called SNX17. The mega‐complex has been dubbed ‘Commander’, and plays an important role in endosomal trafficking of many receptors including integrins, lipoprotein receptors, ATP7A copper transporters, ENaC epithelial sodium channels, and amyloid precursor protein and other receptors. In this seminar I will discuss our work towards an understanding of the molecular basis for how Commander is assembled, interacts with transmembrane cargos, and regulates their recycling or degradation.