Crystal structure of the multifunctional Gβ5–RGS9 complex

Abstract

Regulators of G-protein signaling (RGS) proteins enhance the intrinsic GTPase activity of G protein α (Gα) subunits and are vital for proper signaling kinetics downstream of G protein–coupled receptors (GPCRs). R7 subfamily RGS proteins specifically and obligately dimerize with the atypical G protein β5 (Gβ5) subunit through an internal G protein γ (Gγ)-subunit–like (GGL) domain. Here we present the 1.95-Å crystal structure of the Gβ5–RGS9 complex, which is essential for normal visual and neuronal signal transduction. This structure reveals a canonical RGS domain that is functionally integrated within a molecular complex that is poised for integration of multiple steps during G-protein activation and deactivation.

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Figure 1: Structure of Gβ5–RGS9.
Figure 2: RGS9 N-terminal lobe.
Figure 3: Conserved Gα binding interface on Gβ5.
Figure 4: Gγ-subunit–like (GGL) domains and Gγ subunits are structurally equivalent.
Figure 5: The RGS9-RGS domain interfaces with Gβ5 and activated Gα subunits.
Figure 6: Membrane orientation of the Gβ5–RGS9 complex.

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Acknowledgements

We thank L. Betts for suggestions in analyzing diffraction data. Data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.ser-cat.org/members.html. We thank the SER-CAT beamline staff for assistance in data collection. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences. This research was funded by grants from the US National Institutes of Health (P01-GM65533 and R01-GM081881 to J.S. and T.K.H.), the American Cancer Society (PF-06-034-01-GMC to M.L.C) and the University of North Carolina Lineberger Comprehensive Cancer Center (M.L.C.).

Author information

M.L.C., J.T.S., D.P.S., T.K.H. and J.S. conceived, performed and analyzed experiments, and co-wrote the manuscript. S.G. assisted with construct design.

Correspondence to John Sondek.

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Cheever, M., Snyder, J., Gershburg, S. et al. Crystal structure of the multifunctional Gβ5–RGS9 complex. Nat Struct Mol Biol 15, 155–162 (2008). https://doi.org/10.1038/nsmb.1377

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