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Membrane-dependent signal integration by the Ras activator Son of sevenless

Nature Structural & Molecular Biology volume 15, pages 452–461 (2008)Cite this article

An Erratum to this article was published on 01 June 2008

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Abstract

The kinetics of Ras activation by Son of sevenless (SOS) changes profoundly when Ras is tethered to membranes, instead of being in solution. SOS has two binding sites for Ras, one of which is an allosteric site that is distal to the active site. The activity of the SOS catalytic unit (SOScat) is up to 500-fold higher when Ras is on membranes compared to rates in solution, because the allosteric Ras site anchors SOScat to the membrane. This effect is blocked by the N-terminal segment of SOS, which occludes the allosteric site. We show that SOS responds to the membrane density of Ras molecules, to their state of GTP loading and to the membrane concentration of phosphatidylinositol-4,5-bisphosphate (PIP2), and that the integration of these signals potentiates the release of autoinhibition.

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Figure 1: SOS structure.
Figure 2: The rate of SOScat-catalyzed nucleotide exchange is increased dramatically when Ras is tethered to membranes.
Figure 3: The membrane-dependent increase in the rate of SOScat-catalyzed Ras exchange is a function of the surface density of Ras.
Figure 4: Membrane localization of SOScat by allosteric Ras binding in cells.
Figure 5: The substrate Ras molecule and the activating Ras molecule both need to be tethered to the membrane for maximal SOS activity.
Figure 6: Activity of SOS constructs containing N-terminal regulatory domains.
Figure 7: PIP2-dependent activation of SOS.
Figure 8: The Noonan syndrome mutant, SOSHDPC(R552G), is responsive to the membrane density of PIP2.
Figure 9: The integration of several membrane-localization signals in the activation of Ras and SOS.

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Change history

  • 15 May 2008

    In the version of this article initially published, the concentration units reported in Figure 7b,c should be nM, not nm. The green data series in Figure 7b should be labeled “SOScat”. In addition, on page 452 of the article, the affiliation address for William J. Galush and Jay T. Groves was incorrect. Their correct address is Department of Chemistry, University of California, Berkeley, California 94720, USA. Finally, the last sentence of the Acknowledgments listed incorrect funding information. The last sentence should read, “J.T.G. and W.J.G. are supported by Chemical Sciences, Geosciences and Biosciences Division, Office of Basic Energy Sciences of the US Department of Energy under Contract No. DE_AC03-76SF00098, and D.B.-S. by NIH GM078266.” These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank T. Freedman, O. Kuchment, N. Endres, X. Zhang and M. Lamers for helpful discussions; and D. King for MS. J.G. is supported by the Molecular Biophysics US National Institutes of Health (NIH) grant T32 GM008295. J.T.G. and W.J.G. are supported by Chemical Sciences, Geosciences and Biosciences Division, Office of Basic Energy Sciences of the US Department of Energy under Contract No. DE_AC03-76SF00098, and D.B.-S. by NIH GM078266.

Author information

Author notes

  1. Holger Sondermann

    Present address: Present address: Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.,

  2. Jodi Gureasko and William J Galush: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Cell Biology, Department of Chemistry, and Howard Hughes Medical Institute, QB3 Institute, 176 Stanley Hall, University of California, Berkeley, 94720, California, USA

    Jodi Gureasko, Holger Sondermann & John Kuriyan

  2. Department of Chemistry, University of California, Berkeley, 94720, California, USA

    William J Galush & Jay T Groves

  3. Department of Biochemistry, New York University School of Medicine, New York, 10016, New York, USA

    Sean Boykevisch & Dafna Bar-Sagi

  4. Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, 94720, California, USA

    Jay T Groves & John Kuriyan

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  1. Jodi Gureasko
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Corresponding authors

Correspondence to Dafna Bar-Sagi, Jay T Groves or John Kuriyan.

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Gureasko, J., Galush, W., Boykevisch, S. et al. Membrane-dependent signal integration by the Ras activator Son of sevenless. Nat Struct Mol Biol 15, 452–461 (2008). https://doi.org/10.1038/nsmb.1418

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