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The structural basis of the activation of Ras by Sos

Nature volume 394, pages 337–343 (1998)Cite this article

Abstract

The crystal structure of human H-Ras complexed with the Ras guanine-nucleotide-exchange-factor region of the Son of sevenless (Sos) protein has been determined at 2.8 Å resolution. The normally tight interaction of nucleotides with Ras is disrupted by Sos in two ways. First, the insertion into Ras of an α-helix from Sos results in the displacement of the Switch 1 region of Ras, opening up the nucleotide-binding site. Second, side chains presented by this helix and by a distorted conformation of the Switch 2 region of Ras alter the chemical environment of the binding site for the phosphate groups of the nucleotide and the associated magnesium ion, so that their binding is no longer favoured. Sos does not impede the binding sites for the base and the ribose of GTP or GDP, so the Ras–Sos complex adopts a structure that allows nucleotide release and rebinding.

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Figure 1: Sequence alignment of Ras-binding exchange factors with residue numbers of human (hu) Sos1 indicated.
Figure 2: The complex of human H-Ras with the exchange-factor region of human Sos1.
Figure 3: Interface surfaces of the Ras–Sos complex.
Figure 4: A schematic representation of the differences in the Switch 2 regions of a Ras–GTP analogue and Ras–Sos.
Figure 5: Interactions at the nucleotide-binding site.
Figure 6: Comparison of Ras complexed with Sos and a GTP analogue.

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Acknowledgements

We thank L. Leighton and M. Uy for technical assistance; J. Bonanno, S. K. Burley, R.H. Chen, X. Chen, E. Conti, S. Corbalan-Garcia, D. Galron, B. Hall, M. Huse, S. Jacques, D. Jeruzalmi, C.-H. Lee, S. Soisson, H. Yamaguchi, S.-S. Yang and Y. Zhang for advice and help; L. Berman, R. Sweet, the staff of NSLS and CHESS for help with synchrotron data collection; and A. Wittinghofer and R. H. Cool for sharing a manuscript prior to publication. P.A.B.-S. is supported by grants for the Cystic Fibrosis Foundation and the NIH. D.B.-S. acknowledges grant support from the NIH.

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Authors and Affiliations

  1. Laboratories of Molecular Biophysics, New York, 10021, New York, USA

    P. Ann Boriack-Sjodin & John Kuriyan

  2. Howard Hughes Medical Institute, The Rockefeller University, New York, 10021, New York, USA

    John Kuriyan

  3. Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, 11794, New York, USA

    S. Mariana Margarit & Dafna Bar-Sagi

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Boriack-Sjodin, P., Margarit, S., Bar-Sagi, D. et al. The structural basis of the activation of Ras by Sos. Nature 394, 337–343 (1998). https://doi.org/10.1038/28548

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