Derivative of f bar of z bar8/22/2023 For the SNX-BAR subgroup, the PX domain resides alongside a carboxy-terminal Bin/Amphiphysin/Rvs (BAR) domain ( Carlton et al, 2004), which forms a rigid curved structure upon dimerization, that binds to membrane surfaces that display the corresponding level of membrane curvature ( Peter et al, 2004). SNXs are a large family of proteins classified by the presence of a phosphoinositide-binding phox homology (PX) domain ( Cozier et al, 2002 Rutherford et al, 2006 Teasdale and Collins, 2012). One family of proteins providing new insight into these questions is the SNX-BAR subgroup of sorting nexins (SNXs Carlton and Cullen, 2005 Seet and Hong, 2006 Cullen, 2008 van Weering et al, 2010). How such a complex tubular–vesicular arrangement is generated and how individual tubules maintain their molecular identities during the processes of protein sorting and membrane trafficking remains, on the whole, unclear. These tubular/vesicular membrane profiles constitute molecularly distinct sorting platforms for the recycling of proteins back to the plasma membrane or to the trans-Golgi network (TGN Geuze et al, 1983). Endosomal sorting is achieved in the tubular endosomal network (TEN), a complex arrangement of tubular and vesicular structures that surrounds the endosomal vacuole ( Wall et al, 1980). Our data provide insight into the molecular mechanism that generates and organizes the tubular endosomal network.Įndosomal sorting is an essential process for maintaining cellular homeostasis with deregulated sorting underlying a variety of pathologies, including neurodegenerative diseases and cancer ( Huotari and Helenius, 2011). 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. 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. 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. 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. For the SNX-BAR subgroup, a Bin/Amphiphysin/Rvs (BAR) domain is vital for formation/stabilization of tubular subdomains that mediate cargo recycling. Sorting nexins (SNXs) are regulators of endosomal sorting.
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