Abstract
THE Src-homology-3 (SH3) domains of the Caenorhabditis elegans protein SEM-5 and its human and Drosophila homologues, Grb2 and Drk (refs 1–4), bind proline-rich sequences found in the nucleotide-exchange factor Sos as part of their proposed function linking receptor tyrosine kinase activation to Ras activation5–7. Here we report the crystal structure at 2.0 Å resolution of the carboxyterminal SH3 domain from SEM-5 complexed to the mSos-derived amino-acid sequence PPPVPPRRR. The peptide is found to bind in an orientation ('minus') that is precisely opposite to that observed previously ('plus' orientation) in other SH3–peptide complexes8,9. This novel ability of peptide-recognition proteins to recognize peptides in two distinct modes may play an important role in the signalling specificity of pathways involving SH3 domains. Comparison of this structure with other SH3 complexes reveals how a conserved binding face can be used to recognize peptides in different orientations, and why the Sos peptide binds in this particular orientation.
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References
Clark, S. G., Stern, M. J. & Horvitz, H. R. Nature 356, 340–344 (1992).
Simon, M. A., Dodson, G. S. & Rubin, G. M. Cell 73, 169–177 (1993).
Olivier, J. P. et al. Cell 73, 179–191 (1993).
Lowenstein, E. J. et al. Cell 70, 431–442 (1992).
Egan, S. E. et al. Nature 363, 45–51 (1993).
Rozakis-Adcock, M. et al. Nature 363, 79–83 (1993).
Li, N. et al. Nature 363, 83–85 (1993).
Yu, H. et al. Cell 76, 933–945 (1994).
Musacchio, A., Saraste, M. & Wilmanns, M. Nature struct. Biol. 1, 546–551 (1994).
Noble, M. E. M. et al. EMBO J. 12, 2617–2624 (1993).
Ponder, J. W. & Richards, F. M. J. molec. Biol. 193, 775–791 (1987).
Dunbrack, R. L. & Karplus, M. J. molec. Biol. 230, 542–574 (1993).
Richards, F. M. & Lim, W. A. Q. Rev. Biophys. 26, 423–498 (1993).
Zvelebil, M. J. J. & Thorton, J. M. Q. Rev. Biophys. 26, 333–363 (1993).
Ren, R. et al. Science 259, 1157–1161 (1993).
Gout, I. et al. Cell 75, 25–36 (1993).
Hodel, A., Kim, S. H. & Brünger, A. T. Acta crystallogr. A48, 851–858 (1992).
Ferrin, T. E. et al. J. molec. Graphics 6, 13–27 (1988).
Nicholls, A., Sharp, K. A. & Honig, B. Proteins Struct. Funct. Genet. 11, 281–296 (1991).
Carson, M. J. appl. Crystallogr. 24, 958–961 (1991).
Lim, W. A., Fox, R. O. & Richards, F. M. Protein Sci. 3, 1261–1266 (1994).
Navaza, J. Acta crystallogr. A43, 645–653 (1987).
Musacchio, A. et al. Nature 359, 851–855 (1992).
Brünger, A. T., Kuriyan, J. & Karplus, M. Science 235, 458–460 (1987).
Brünger, A. T. Nature 355, 472–474 (1992).
Lim, W. A. & Richards, F. M. Nature struct. Biol. 1, 221–225 (1994).
Wittekind, M. et al. Biochemistry (in the press).
Terasawa, H. et al. Nature struct. Biol. (in the press).
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Lim, W., Richards, F. & Fox, R. Structural determinants of peptide-binding orientation and of sequence specificity in SH3 domains. Nature 372, 375–379 (1994). https://doi.org/10.1038/372375a0
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DOI: https://doi.org/10.1038/372375a0
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