Research article

Exploring allosteric coupling in the α-subunit of Heterotrimeric G proteins using evolutionary and ensemble-based approaches

Kemal Sayar^1,2 , Özlem Uğur¹ , Tong Liu³ , Vincent J Hilser³ and Ongun Onaran^1,2

¹Ankara University Faculty of Medicine, Department of Pharmacology and Clinical Pharmacology, Sıhhiye 06100, Ankara, Turkey

²Ankara University Faculty of Medicine, and Molecular Biology and Technology Research and Development Unit, Sıhhiye 06100, Ankara, Turkey

³Department of Biochemistry and Molecular Biology, and Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, 77555-1068 USA

author email corresponding author email

BMC Structural Biology 2008, 8:23doi:10.1186/1472-6807-8-23

Published:	2 May 2008

Abstract

Background

Allosteric coupling, which can be defined as propagation of a perturbation at one region of the protein molecule (such as ligand binding) to distant sites in the same molecule, constitutes the most general mechanism of regulation of protein function. However, unlike molecular details of ligand binding, structural elements involved in allosteric effects are difficult to diagnose. Here, we identified allosteric linkages in the α-subunits of heterotrimeric G proteins, which were evolved to transmit membrane receptor signals by allosteric mechanisms, by using two different approaches that utilize fundamentally different and independent information.

Results

We analyzed: 1) correlated mutations in the family of G protein α-subunits, and 2) cooperativity of the native state ensemble of the Gαi1 or transducin. The combination of these approaches not only recovered already-known details such as the switch regions that change conformation upon nucleotide exchange, and those regions that are involved in receptor, effector or Gβγ interactions (indicating that the predictions of the analyses can be viewed with a measure of confidence), but also predicted new sites that are potentially involved in allosteric communication in the Gα protein. A summary of the new sites found in the present analysis, which were not apparent in crystallographic data, is given along with known functional and structural information. Implications of the results are discussed.

Conclusion

A set of residues and/or structural elements that are potentially involved in allosteric communication in Gα is presented. This information can be used as a guide to structural, spectroscopic, mutational, and theoretical studies on the allosteric network in Gα proteins, which will provide a better understanding of G protein-mediated signal transduction.