G protein beta-gamma (Gβγ) subunits anchor to the plasma membrane (PM) through the carboxy-terminal (CT) prenyl group in Gγ. This interaction is crucial for the PM localization and functioning of Gβγ, allowing GPCR-G protein signaling to proceed. The diverse Gγ family has twelve members, and we have recently shown that the signaling efficacies of major Gβγ effectors are Gγ-type dependent. This dependency is due to the distinct series of membrane-interacting abilities of Gγ. However, the molecular process allowing for Gβγ subunits to exhibit a discrete and diverse range of Gγ-type dependent membrane affinities is unclear and cannot be explained only using the type of prenylation. The present work explores the unique designs of membrane-interacting CT-residues in Gγ as a major source for this Gγ-type dependent Gβγ signaling. Despite the type of prenylation, results show signaling efficacy at the PM, and associated cell behaviors of Gβγ are governed by crucially located specific amino acids in the 5–6 residue pre-prenylation region of Gγ. The provided molecular picture of Gγ–membrane interactions may explain how cells gain Gγ-type dependent G protein-GPCR signaling as well as how Gβγ elicits selective signaling at various subcellular compartments.
