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Optimization of specificity in a cellular protein interaction network by negative selection

Nature volume 426, pages 676–680 (2003)Cite this article

Abstract

Most proteins that participate in cellular signalling networks contain modular protein-interaction domains. Multiple versions of such domains are present within a given organism1: the yeast proteome, for example, contains 27 different Src homology 3 (SH3) domains2. This raises the potential problem of cross-reaction. It is generally thought that isolated domain–ligand pairs lack sufficient information to encode biologically unique interactions, and that specificity is instead encoded by the context in which the interaction pairs are presented3,4. Here we show that an isolated peptide ligand from the yeast protein Pbs2 recognizes its biological partner, the SH3 domain from Sho1, with near-absolute specificity—no other SH3 domain present in the yeast genome cross-reacts with the Pbs2 peptide, in vivo or in vitro. Such high specificity, however, is not observed in a set of non-yeast SH3 domains, and Pbs2 motif variants that cross-react with other SH3 domains confer a fitness defect, indicating that the Pbs2 motif might have been optimized to minimize interaction with competing domains specifically found in yeast. System-wide negative selection is a subtle but powerful evolutionary mechanism to optimize specificity within an interaction network composed of overlapping recognition elements.

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Figure 1: The yeast high-osmolarity pathway as a system for studying SH3 network specificity.
Figure 2: The Sho1 SH3 domain can only be functionally replaced by extra-species (non-S. cerevisiae) SH3 domains.
Figure 3: Model: role of proteome-wide negative selection in interaction network specificity.
Figure 4: Pbs2 proline-rich motif is optimized to avoid cross-reactivity with other yeast SH3 domains.

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Acknowledgements

We thank A. Davidson and members of the Davidson laboratory, I. Herskowitz, P. Y. Kwok, E. O'Shea, A. Sali, K. Yamamoto, R. Zuckerman, P. Chien, K. Chak, R. Bhattacharyya, J. Dueber, N. Sallee, B. Yeh, and members of the Lim laboratory for assistance and discussion. This work was supported by grants from the NIH and the Packard Foundation. S.-H.P. is a Jane Coffin Child Fellow. A.Z. is supported by the UCSF Medical Scientist Training Program.

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Authors and Affiliations

  1. Program in Biological Sciences, University of California, San Francisco, 600 16th Street, California, 94143-2240, San Francisco, USA

    Ali Zarrinpar

  2. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 600 16th Street, California, 94143-2240, San Francisco, USA

    Ali Zarrinpar, Sang-Hyun Park & Wendell A. Lim

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Correspondence to Wendell A. Lim.

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Zarrinpar, A., Park, SH. & Lim, W. Optimization of specificity in a cellular protein interaction network by negative selection. Nature 426, 676–680 (2003). https://doi.org/10.1038/nature02178

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