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Evolutionarily conserved networks of residues mediate allosteric communication in proteins

Nature Structural Biology volume 10, pages 59–69 (2003)Cite this article

A Corrigendum to this article was published on 01 March 2003

Abstract

A fundamental goal in cellular signaling is to understand allosteric communication, the process by which signals originating at one site in a protein propagate reliably to affect distant functional sites. The general principles of protein structure that underlie this process remain unknown. Here, we describe a sequence-based statistical method for quantitatively mapping the global network of amino acid interactions in a protein. Application of this method for three structurally and functionally distinct protein families (G protein–coupled receptors, the chymotrypsin class of serine proteases and hemoglobins) reveals a surprisingly simple architecture for amino acid interactions in each protein family: a small subset of residues forms physically connected networks that link distant functional sites in the tertiary structure. Although small in number, residues comprising the network show excellent correlation with the large body of mechanistic data available for each family. The data suggest that evolutionarily conserved sparse networks of amino acid interactions represent structural motifs for allosteric communication in proteins.

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Figure 1: A statistical perturbation method for measuring interactions between residues in proteins.
Figure 2: Mapping statistical coupling for the Tyr296 perturbation in GPCRs (Fig. 1g) onto the structure of a representative member of the protein family, bovine rhodopsin.
Figure 3: Cluster analysis of statistical coupling in the GPCR family.
Figure 4: A physically connected network of coupling between residues in the GPCR family.
Figure 6: Structural mapping of the two co-evolving clusters of residues in the chymotrypsin family of serine proteases.
Figure 5: A global analysis of statistical coupling in the chymotrypsin-family of serine proteases.
Figure 7: A global analysis of statistical coupling in the hemoglobin family.
Figure 8: Structural mapping of the two clusters of coupled residues in the hemoglobin family.

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Acknowledgements

We thank J. Albanesi, M. Brown, A. Gilman, and members of the Ranganathan lab for critical reading of the manuscript. This work was partially supported by a grant from the Robert A. Welch Foundation to R.R., who is also a recipient of the Burroughs-Wellcome Fund New Investigator Award in the Basic Pharmacological Sciences and the Mallinckrodt Scholar Award. M.A.W. is a Research Associate and R.R. is an Associate Investigator of the Howard Hughes Medical Institute.

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  1. Gürol M. Süel, Steve W. Lockless, Mark A. Wall and Rama Ranganathan: These authors contributed equally to this work.

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  1. Howard Hughes Medical Institute and Department of Pharmacology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390-9050, Texas, USA

    Gürol M. Süel, Steve W. Lockless, Mark A. Wall & Rama Ranganathan

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Süel, G., Lockless, S., Wall, M. et al. Evolutionarily conserved networks of residues mediate allosteric communication in proteins. Nat Struct Mol Biol 10, 59–69 (2003). https://doi.org/10.1038/nsb881

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