Since its discovery by Louis Pasteur in 1848 (1), chirality has been—and still is to this day—one major topic for chemists and biochemists alike. Many chirality-related phenomena, from alteration of polarized light to enantioselectivity of enzymes for their substrate, form an integral part of today's university courses in chemical and biological sciences. Similar to the enzymes in charge of their synthesis, phospholipids, glycolipids, and sterols found in biological membranes are chiral. However, even though the effect of chirality on the organization of lipid membranes has been studied (see for example, Weis and McConnell (2)), little is known about the impact of lipid configuration on biological function. In this issue of the Biophysical Journal, Schutte et al. (7) resort to cutting-edge chemical synthesis to generate the unnatural enantiomer of Globotriaosylceramide 3 (Gb3, a glycolipid of established biological importance), and investigate the consequences of changing Gb3 configuration on membrane binding and deformation by Shiga toxin, for which Gb3 is the biological receptor. The Shiga toxin of the bacteria Shigella dysenteriae is a protein that binds Gb3 on the plasma membrane via its B subunit (STxB), and forms membrane-bound protein domains. Importantly, by doing so Shiga toxin induces its own internalization in cells by causing inward curvatures of membranes. This phenomenon is reproduced in vitro by adding STxB to giant unilamellar vesicles (GUVs) containing a small fraction of Gb3, in conditions favoring low membrane tension (3). Like in cells, Gb3 used in in vitro assays is the Gb3-R enantiomer. By replacing Gb3-R with its unnatural enantiomer Gb3-S, Schutte et al. (7) observe that STxB-induced tubulation of GUVs is significantly enhanced, based on experiments with a total of 1253 GUVs. Although the affinity of STxB was the same for Gb3-S as for its natural counterpart, reflectometric interference spectroscopy suggested that the domain height and protein distribution in Gb3-S membranes significantly differed from that in Gb3-R membranes. Those observations were confirmed by atomic force microscopy (AFM) imaging of STxB domains formed in mica-supported planar bila-yers composed of DOPC, DPPC, and Gb3. Taken together, those observation show that, in the words of the authors, .Gb3-R favorably induces large
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