The role of electrostatic interactions in the regulation of the membrane association of G protein beta gamma heterodimers

J Biol Chem. 2001 Nov 30;276(48):45153-9. doi: 10.1074/jbc.M101784200. Epub 2001 Sep 13.

Abstract

In this paper we report calculations of electrostatic interactions between the transducin (G(t)) betagamma heterodimer (G(t)betagamma) and phospholipid membranes. Although membrane association of G(t)betagamma is due primarily to the hydrophobic penetration into the membrane interior of a farnesyl chain attached to the gamma subunit, structural studies have revealed that there is a prominent patch of basic residues on the surface of the beta subunit surrounding the site of farnesylation that is exposed upon dissociation from the G(t)alpha subunit. Moreover, phosducin, which produces dissociation of G(t)betagamma from membranes, interacts directly with G(t)betagamma 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 G(t)betagamma has a large net negative charge (-12). 2) This electrostatic attraction positions G(t)betagamma so that residues implicated in mediating the interaction of G(t)betagamma with its membrane-bound effectors are close to the membrane surface. 3) The binding of phosducin to G(t)betagamma diminishes the membrane partitioning of G(t)betagamma 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 Gbetagamma and phosducin isoforms as well.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Membrane / metabolism
  • Dimerization
  • Dose-Response Relationship, Drug
  • Eye Proteins / chemistry
  • GTP-Binding Protein Regulators
  • GTP-Binding Protein beta Subunits*
  • GTP-Binding Protein gamma Subunits*
  • Heterotrimeric GTP-Binding Proteins / chemistry*
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • Humans
  • Kinetics
  • Lipid Metabolism
  • Models, Chemical
  • Models, Molecular
  • Models, Statistical
  • Molecular Sequence Data
  • Phosphoproteins / chemistry
  • Protein Binding
  • Protein Isoforms
  • Rats
  • Static Electricity
  • Thermodynamics

Substances

  • Eye Proteins
  • G-protein Beta gamma
  • GTP-Binding Protein Regulators
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Phosphoproteins
  • Protein Isoforms
  • phosducin
  • Heterotrimeric GTP-Binding Proteins