Compartmentalisation is a defining feature of all eukaryotic cells, and we have evolved highly sophisticated protein machineries to control the flow of transmembrane molecules and membrane lipids between different organelles. Disruption of these processes are linked to numerous diseases including neurodegenerative disorders, pathogen invasion and cancer. We are determining how these trafficking machineries are assembled and regulated at the molecular level through a combination of structural biology, biophysical, and cell biology approaches. We describe our most recent work on critical protein sorting machineries – the retromer complex and the sorting nexins (SNXs) - regulating endosomal membrane recycling and cellular homeostasis. We have defined sorting signals required for endosomal recycling by the SNX27-retromer complex, how this is regulated by post-translational phosphorylation, and the structural basis for SNX27-retromer-cargo assembly (1). Recently we have also begun to study that assembly of retromer and sorting nexin proteins on artificial membranes using cryo-electron microscopy and sub-tomogram averaging, revealing details of the architecture of the functional membrane-associated complexes at nanometre resolution.
(1) T. Clairfeuille, et al., 2016, Nat. Struct. Mol. Biol.