posted 09. July 2003 17:51                    

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Evolutionarily conserved networks of residues mediate allosteric communication in proteins
Gürol M. Süel1, 2, Steve W. Lockless1, 2, Mark A. Wall2 & Rama Ranganathan2

1. These authors contributed equally to this work.
2. Howard Hughes Medical Institute and Department of Pharmacology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9050, USA.
Correspondence should be addressed to R Ranganathan. e-mail: rama@chop.swmed.edu

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.

Communication between distant sites in allosteric proteins is fundamental to their function and often defines the biological role of a protein family. In signaling proteins, it represents information transfer — the transmission of signals initiated at one functional surface to a distinct surface mediating downstream signaling. For example, ligand binding at an externally accessible site in G protein–coupled receptors (GPCRs) reliably triggers structural changes at distant cytoplasmic domains that mediate interaction with heterotrimeric G proteins1, 2. Studies in many other protein systems indicate that long-range interactions of amino acids also are important in binding (and catalytic) specificity. Substrate recognition in the chymotrypsin family of serine proteases3, 4, the tuning of antibody specificity through B-cell maturation5 and the cooperativity of oxygen binding in hemoglobin6-9 all depend not only on residues directly contacting substrate, but also on distant residues located in supporting loops and other secondary structural elements. Crystallographic studies in all of these systems5, 9-11 indicate that the distant residues participating in substrate recognition do so by acting through intervening positions to control the structure of the substrate-binding site. These long-range interactions are remarkable because many other sites, even if closer to active site residues, show little contribution to function. Taken together, these studies indicate that proteins are complex materials in which perturbations at sites — for example, substrate binding, covalent modification or mutation — may cause conformational change to happen in a fracture-like manner that is not obvious in atomic structures. From a biological point of view, these fractures represent the energy transduction mechanisms that mediate signal flow, allosteric regulation and specificity in molecular recognition.

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