van Weering, Jan R.T.8; Sessions, Richard B.8; Traer, Colin J.8; Kloer, Daniel P.9; Bhatia, Vikram K.4; Stamou, Dimitrios10; Carlsson, Sven R.6; Hurley, James H.7; Cullen, Peter J.8
1 Department of Chemistry, Faculty of Science, Københavns Universitet2 University of Bristol3 Syngenta4 Novozymes A/S5 Administration, Department of Chemistry, Faculty of Science, Københavns Universitet6 Umeå University7 National Institutes of Health8 University of Bristol9 Syngenta10 Administration, Department of Chemistry, Faculty of Science, Københavns Universitet
Sorting nexins (SNXs) are regulators of endosomal sorting. For the SNX-BAR subgroup, a Bin/Amphiphysin/Rvs (BAR) domain is vital for formation/stabilization of tubular subdomains that mediate cargo recycling. Here, by analysing the in vitro membrane remodelling properties of all 12 human SNX-BARs, we report that some, but not all, can elicit the formation of tubules with diameters that resemble sorting tubules observed in cells. We reveal that SNX-BARs display a restricted pattern of BAR domain-mediated dimerization, and by resolving a 2.8 Å structure of a SNX1-BAR domain homodimer, establish that dimerization is achieved in part through neutralization of charged residues in the hydrophobic BAR-dimerization interface. Membrane remodelling also requires functional amphipathic helices, predicted to be present in all SNX-BARs, and the formation of high order SNX-BAR oligomers through selective 'tip-loop' interactions. Overall, the restricted and selective nature of these interactions provide a molecular explanation for how distinct SNX-BAR-decorated tubules are nucleated from the same endosomal vacuole, as observed in living cells. Our data provide insight into the molecular mechanism that generates and organizes the tubular endosomal network.
E M B O Journal, 2012, Vol 31, Issue 23, p. 4466-4480