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Previous model studies of peptides and proteins have shown that protein-lipid interactions, primarily involving amino acid side chains near the membrane-water interface, modulate the position of transmembrane helices in bilayers. The present study examines whether such interfacial side chains stabilize the signaling states of a transmembrane signaling helix in a representative receptor, the aspartate receptor of bacterial chemotaxis. To examine the functional roles of signaling helix side chains at the periplasmic and cytoplasmic membrane-water interfaces, arginine and cysteine substitutions were scanned through these two interfacial regions. The chemical reactivities of the cysteine residues were first measured to determine the positions at which the helix crosses the membrane-water interface in both the periplasmic and cytoplasmic compartments. Subsequently, two antisymmetric in vitro activity measurements were carried out to determine the effect of each interfacial arginine or cysteine substitution on receptor signaling. Substitutions that stabilize the receptor on-state cause upregulation of receptor-coupled kinase activity and inhibition of methylation at receptor adaptation sites, while substitutions that stabilize the off-state have the opposite effects on these two activities. Notably, four substitutions at aromatic tryptophan and phenylalanine positions buried in the membrane near the membrane-water interface were found to stabilize the native on- or off-signaling state. The striking ability of these substitutions to drive the receptor toward a specific signaling state indicates that interfacial side chains are highly optimized to correctly position the native signaling helix in the membrane and to allow normal switching between the on- and off-signaling states. The analogous substitutions in model transmembrane helices are known to drive small piston-type displacements of the helix normal to the membrane. Thus, the simplest molecular interpretation of the present findings is that the signal-stabilizing substitutions drive piston displacements of the signaling helix, providing further support for the piston model for transmembrane signaling in bacterial chemoreceptors. More generally, the findings indicate that the interfacial phenylalanine, tryptophan, and arginine side chains widespread in the transmembrane alpha-helices of receptors, channels, and transporters can play important roles in modulating transitions between signaling and conformational states.

Side Chains at the Membrane−Water Interface Modulate the Signaling State of a Transmembrane Receptor