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Structural basis for the geometry-driven localization of a small protein

Significance Despite extensive studies of protein trafficking across length scales of many microns, how proteins correctly localize within the smaller length scales of bacterial cells is still poorly understood. Recently, we proposed that slight membrane curvature, defined by the surface geometry of a bacterium, can drive the localization of certain shape-sensing proteins. Here, we developed an assay to quantify membrane curvature recognition by the small bacterial protein SpoVM and used NMR to determine the structural basis of curvature recognition. NMR and molecular dynamics simulations suggested a model wherein unusually deep membrane insertion allows the protein to sense subtle acyl chain packing differences between differently curved membranes, a distinct curvature-sensing mechanism from those used by proteins that sense high membrane curvature. In bacteria, certain shape-sensing proteins localize to differently curved membranes. During sporulation in Bacillus subtilis, the only convex (positively curved) surface in the cell is the forespore, an approximately spherical internal organelle. Previously, we demonstrated that SpoVM localizes to the forespore by preferentially adsorbing onto slightly convex membranes. Here, we used NMR and molecular dynamics simulations of SpoVM and a localization mutant (SpoVMP9A) to reveal that SpoVM’s atypical amphipathic α-helix inserts deeply into the membrane and interacts extensively with acyl chains to sense packing differences in differently curved membranes. Based on binding to spherical supported lipid bilayers and Monte Carlo simulations, we hypothesize that SpoVM’s membrane insertion, along with potential cooperative interactions with other SpoVM molecules in the lipid bilayer, drives its preferential localization onto slightly convex membranes. Such a mechanism, which is distinct from that used by high curvature-sensing proteins, may be widely conserved for the localization of proteins onto the surface of cellular organelles.