From: Josh Bembenek (jbembe@hotmail.com)
Date: Wed Jul 09 2003 - 17:54:52 EDT
The following work identifies residues within allosteric proteins that are
important for transmitting binding energy between proteins. It identifies
multiple residues that are involved at the same time.
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.
This is work raises a very relevant question for protein evolution. If
allosteric proteins in general function by engaging conduits of
energetically coupled residues to transmit binding energies and convey
signals, how can these proteins evolve in a stepwise fashion? If a mutation
disrupts the conductivity of these allosteric conduits, then multiple
mutations must occur simultaneously in order for the protein to maintain
allosteric function. Also, when thinking about signaling networks that
contain multiple allosteric proteins, then the pathways may need to be
modified through several proteins, not just one. Any comments on this?
Note, that these conduits are recognized because the amino acids represented
in the sequence database appear together with higher frequency (i.e.
position x and y always appear as these two amino acids because they are
transmitting allosteric information through the protein.) In order to
modify the signal transduction, perhaps multiple residues in the conduit
must be modified before the appropriate function is realized? This creates
some barriers to evolving in a step-wise fashion.
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