Protein Evolution

From: Josh Bembenek (jbembe@hotmail.com)
Date: Wed Jul 09 2003 - 17:54:52 EDT

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    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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