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G-protein diseases furnish a model for the turn-on switch

Nature volume 394, pages 35–38 (1998)Cite this article

Abstract

How does a trimeric G protein on the inside of a cell membrane respond to activation by a transmembrane receptor? G-protein mutations in patients with hypertension and inherited endocrine disorders enhance or block signals from stimulated receptors. In combination with three-dimensional crystal structures and results from biochemical experiments, the phenotypes produced by these mutations suggest a model for the molecular activation mechanism that relays hormonal and sensory signals transmitted by many transmembrane receptors.

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Figure 1: The GTPase cycle of trimeric G proteins.
Figure 2: The postulated3,8 orientation of a G-protein trimer to a transmembrane receptor.
Figure 3: Surfaces of Gα·GDP that may play a key role in the GDP/GTP exchange reaction.
Figure 4: Contacts between Gβγ (left) and Gα·GDP (right).
Figure 5: Different conformations of Gα·GDP in the trimer3 and GTP-bound Gα (ref. 18).

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References

  1. Hamm, H. E. The many faces of G protein signaling. J. Biol. Chem. 273, 669–672 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Sprang, S. R. Gprotein mechanisms: Insights from structural analysis. Annu. Rev. Biochem. 66, 639–678 (1997).

    Article  CAS  Google Scholar 

  3. Lambright, D. G. et al. The 2.0 Å crystal structure of a heterotrimeric G protein. Nature 379, 311–319 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Baldwin, J. M., Schertler, G. F. & Unger, V. M. An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors. J. Mol. Biol. 272, 144–164 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Hargrave, P. A., Hamm, H. E. & Hofmann, K. P. Interaction of rhodopsin with the G-protein, transducin. Bioessays 15, 43–50 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Fahmy, K., Siebert, F. & Sakmar, T. P. Photoactivated state of rhodopsin and how it can form. Biophys. Chem. 56, 171–181 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Strader, C. D., Fong, T. M., Graziano, M. P. & Tota, M. R. The family of G-protein-coupled receptors. FASEB J. 9, 745–754 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Bourne, H. R. How receptors talk to trimeric G proteins. Curr. Opin. Cell Biol. 134–142 (1997).

  9. Bourne, H. R., Sanders, D. A. & McCormick, F. The GTPase superfamily. A conserved switch for diverse cell functions. Nature 348, 125–132 (1990).

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Bourne, H. R., Sanders, D. A. & McCormick, F. The GTPase superfamily: Conserved structure and molecular mechanism. Nature 349, 117–127 (1991).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Bourne, H. R. The arginine finger strikes again. Nature 389, 673–674 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Bohm, A., Gaudet, R. & Sigler, P. B. Structural aspects of heterotrimeric G-protein signaling. Curr. Opin. Biotechnol. 8, 480–487 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Scheffzek, K. et al. The Ras–RasGAP complex: Structural basis for GTPase activation and its loss in oncogenic ras mutants. Science 277, 333–338 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Sondek, J., Lambright, D. G., Noel, J. P., Hamm, H. E. & Sigler, P. B. GTPase mechanism of G proteins from the 1.7-Å crystal structure of transducin α-GDP-A1F4−. Nature 372, 276–279 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  15. Coleman, D. E. et al. Structure of active conformations of Giα1 and the mechanism of GTP hydrolysis. Science 265, 1405–1412 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Tesmer, J. J., Berman, D. M., Gilman, A. G. & Sprang, S. R. Structure of RGS4 bound to AlF4− activated Giα1: stabilization of the transition state for GTP hydrolysis. Cell 89, 251–261 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Lambright, D. G., Noel, J. P., Hamm, H. E. & Sigler, P. B. The 1.8 Å crystal structure of transducin α-GDP: structural determinants for activation of a heterotrimeric G-protein α-subunit. Nature 369, 621–628 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Noel, J. P., Hamm, H. E. & Sigler, P. B. The 2.2 Å crystal structure of transducin α-GTPγS. Nature 366, 654–663 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Sondek, J., Bohm, A., Lambright, D. G., Hamm, H. E. & Sigler, P. B. Crystal structure of a GAprotein βγ dimer at 2.1 Å resolution. Nature 379, 369–374 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Mixon, M. B. et al. Tertiary and quaternary structural changes in Giα1induced by GTP hydrolysis. Science 270, 954–960 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Wall, M. A. et al. The structure of the G protein heterotrimer Giα1β1γ1. Cell 83, 1047–1058 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Sunahara, R. K., Tesmer, J. J. G., Gilman, A. G. & Sprang, S. R. Crystal structure of the adenylyl cyclase activator, Gsα. Science 278, 1943–1947 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Garcia, P. D., Onrust, R., Bell, S. M., Sakmar, T. P. & Bourne, H. R. Transducin-α C-terminal mutations prevent activation by rhodopsin: A new assay using recombinant proteins expressed in cultured cells. EMBO J. 14, 4460–4469 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Onrust, R. et al. Receptor and βγ binding sites in the α subunit of the retinal G protein transducin. Science 275, 381–384 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Hamm, H. E. et al. Site of G protein binding to rhodopsin mapped with synthetic peptides from the α subunit. Science 241, 832–835 (1988).

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Kawashima, T., Berthet-Colominas, C., Wulff, M., Cusack, S. & Leberman, R. The structure of the Escherichia coli EF-Tu·EF-Ts complex at 2.5 Å resolution. Nature 379, 511–518 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Wang, Y., Jiang, Y., Meyering-Voss, M., Sprinzl, M. & Sigler, P. B. Crystal structure of the EF-Tu·EF-Ts complex from Thermus thermophilus. Nature Struct. Biol. 4, 950–956 (1997).

    Google Scholar 

  28. Iiri, T., Herzmark, P., Nakamoto, J. M., Van Dop, C. & Bourne, H. R. Rapid GDP release from Gsαin patients with gain and loss of endocrine function. Nature 371, 164–168 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  29. Feig, L. A. & Cooper, G. M. Relationship among guanine nucleotide exchange, GTP hydrolysis, and transofrming potential of mutated ras proteins. Mol. Cell. Biol. 8, 2472–2478 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Schwindinger, W. F., Miric, A., Zimmerman, D. & Levine, M. A. Anovel Gsα mutant in a patient with Albright hereditrary osteodystrophy uncouples cell surface receptors from adenylyl cyclase. J. Biol. Chem. 269, 25387–25391 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. West, R. E., Moss, J., Vaughan, M., Liu, T. & Liu, T. Y. Pertussis toxin-catalyzed ADP-ribosylation of transducin. Cysteine-347 is the ADP-ribose acceptor site. J. Biol. Chem. 260, 14428–14430 (1985).

    Article  CAS  PubMed  Google Scholar 

  32. Farrens, D. L., Altenbach, C., Yang, K., Hubbell, W. L. & Khorana, . G. Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science 274, 768–770 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  33. Bae, H. et al. Molecular determinants of selectivity in 5-hydroxytryptamine1Breceptor–G protein interactions. J. Biol. Chem. 272, 32071–32077 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Mazzoni, M. R. & Hamm, H. E. Interaction of transducin with light-activated rhodopsin protects It from proteolytic digestion by trypsin. J. Biol. Chem. 271, 30034–30040 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Denker, B. M., Schmidt, C. J. & Neer, E. J. Promotion of the GTP-liganded state of the Goαprotein by deletion of the C terminus. J. Biol. Chem. 267, 9998–10002 (1992).

    Article  CAS  PubMed  Google Scholar 

  36. Ford, C. E. et al. Molecular basis for interactions of G protein βγ subunits with effectors. Science 280, 1271–1274 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Siffert, W. et al. Association of an allele of a human G-protein β3 subunit gene with hypertension. Nature Genet. 18, 45–48 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Iiri, T. & Bourne, H. R. Gproteins propel surprise. Nature Genet. 18, 45–48 (1998).

    Article  Google Scholar 

  39. Clapham, D. E. & Neer, E. J. Gprotein γβ subunits. Annu. Rev. Pharmacol. Toxicol. 37, 167–203 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Berstein, G. et al. Reconstitution of agonist-stimulated phosphatidylinositol 4,5-bisphosphate hydrolysis using purified m1 muscarinic receptor, Gq/11, and phospholipase C-β1. J. Biol. Chem. 267, 8081–8088 (1992).

    Article  CAS  PubMed  Google Scholar 

  41. Farfel, Z. et al. Pseudohypoparathyroidism, a novel mutation in the βγ-contact region of Gsαimpairs receptor stimulation. J. Biol. Chem. 271, 19653–19655 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Iiri, T., Farfel, Z. & Bourne, H. R. Conditional activation defect of a human Gsαmutant. Proc. Natl Acad. Sci. USA 94, 5656–5661 (1997).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stratton, H. F., Zhou, J., Reed, S. I. & Stone, D. E. The mating-specific Gαprotein of Saccharomyces cerevisiae downregulates the mating signal by a mechanism that is dependent on pheromone and independent of Gβγsequestration. Mol. Cell. Biol. 16, 6325–6337 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Higashijima, T., Ferguson, K. M., Sternweis, P. C., Smigel, M. D. & Gilman, A. G. Effects of Mg2+ an the βγ-subunit on the interactions of guanine nucleotides with G proteins. J. Biol. Chem. 262, 762–766 (1987).

    Article  CAS  PubMed  Google Scholar 

  45. Sternweis, P. C. The active role of beta gamma in signal transduction. Curr. Opin. Cell Biol. 6, 198–203 (1994).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by a Julius Comroe Fellowship (T.I.), grants from the United States–Israel Binational Foundation and the Israeli Ministry of Health (Z.F.), and by NIH grants (H.R.B.).

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Author notes

  1. Taroh Iiri

    Present address: Fourth Department of Internal Medicine, University of Tokyo School of Medicine, 3-28-6 Mejirodai, Bunkyo-tu, Tokyo, 112, Japan

Authors and Affiliations

  1. Departments of Cellular and Molecular Pharmacology and Medicine, University of California, San Francisco, 94143-0450, California, USA

    Taroh Iiri & Henry R. Bourne

  2. Laboratory of Biochemical Pharmacology and Department of Medicine E, Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel

    Zvi Farfel

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Correspondence to Henry R. Bourne.

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Iiri, T., Farfel, Z. & Bourne, H. G-protein diseases furnish a model for the turn-on switch. Nature 394, 35–38 (1998). https://doi.org/10.1038/27831

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