The Role of Electrostatic Interactions in the Regulation of the Membrane Association of G Protein Heterodimers*

In this paper we report calculations of electrostatic interactions between the transducin (Gt) heterodimer (Gt ) and phospholipid membranes. Although membrane association of Gt is due primarily to the hydrophobic penetration into the membrane interior of a farnesyl chain attached to the subunit, structural studies have revealed that there is a prominent patch of basic residues on the surface of the subunit surrounding the site of farnesylation that is exposed upon dissociation from the Gt subunit. Moreover, phosducin, which produces dissociation of Gt from membranes, interacts directly with Gt and introduces a cluster of acidic residues into this region. The calculations, which are based on the finite difference Poisson-Boltzmann method, account for a number of experimental observations and suggest that charged residues play a role in mediating protein-membrane interactions. Specifically, the calculations predict the following. 1) Favorable electrostatic interactions enhance the membrane partitioning due to the farnesyl group by an order of magnitude although Gt has a large net negative charge ( 12). 2) This electrostatic attraction positions Gt so that residues implicated in mediating the interaction of Gt with its membrane-bound effectors are close to the membrane surface. 3) The binding of phosducin to Gt diminishes the membrane partitioning of Gt by an order of magnitude. 4) Lowering the ionic strength of the solution converts the electrostatic attraction into a repulsion. Sequence analysis and homology model building suggest that our conclusions may be generalized to other G and phosducin isoforms as well.