Proteins embedded in the plasma membrane mediate interactions with the cell environment and play decisive
roles in many signaling events. For cell−cell recognition molecules, it is highly likely that their structures and behavior have been
optimized in ways that overcome the limitations of membrane tethering. In particular, the ligand binding regions of these
proteins likely need to be maximally exposed. Here we show by means of atomistic simulations of membrane-bound CD2, a small
cell adhesion receptor expressed by human T-cells and natural killer cells, that the presentation of its ectodomain is highly
dependent on membrane lipids and receptor glycosylation acting in apparent unison. Detailed analysis shows that the underlying
mechanism is based on electrostatic interactions complemented by steric interactions between glycans in the protein and the
membrane surface. The findings are significant for understanding the factors that render membrane receptors accessible for
binding and signaling.