We examined model mixed micelles consisting of the nonionic surfactant n-dodecyl-β-D-maltoside, 3-(3-cholamidopropyl)-dimethylammoniopropane sulfonate, and the cholesterol derivative cholesteryl hemisuccinate (CHS) to identify micellar properties that are correlated with the in vitro conformational stability and activity of the human adenosine A2a receptor, a G-protein coupled receptor. Small-angle neutron scattering was used to determine micellar structure and composition as a function of concentration of the various components, and radioligand binding was used as a sensitive probe for receptor activity. Micelles adopted an oblate ellipsoidal morphology and exhibited a reduction in size and change in curvature upon addition of CHS. Our results show a strong correlation between the number of CHS monomers per micelle and the activity of the receptor reconstituted in those micelles. Micelles that yield optimal human adenosine A2a receptor stability closely mimic the cholesterol composition and thickness of mammalian membranes. Thus, successful reconstitution of the receptor is dependent on both specific lipid-protein interactions and the geometry of the micelle environment. © 2011 by the Biophysical Society.
O’Malley, M. A., Helgeson, M. E., Wagner, N. J., & Robinson, A. S. (2011). The morphology and composition of cholesterol-rich micellar nanostructures determine transmembrane protein (GPCR) activity. Biophysical Journal, 100(2). https://doi.org/10.1016/j.bpj.2010.12.3698