Restricted evolution of proteins

Date: Mon Nov 06 2000 - 11:08:17 EST

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    The following paper is very important in connection with protein
    Douglas D. Axe, "Extreme functional sensitivity to conservative amino
    acid changes on enzyme exteriors", J.Mol.Biol. 301 (2000), 585-95.

    It shows experimentally that by far the largest proportion of
    conceivable evolutionary paths may not be neutral but deleterious.

    Axe's abstract:
    "Mutagenesis studies and alignments of homologous sequences have
    demonstrated that protein function typically is compatible with a
    variety of amino-acid residues at most exterior non-active-site
    positions. These observations have led to the current view that
    functional constraints on sequence are minimal at these positions. Here,
    it is shown that this inference assumes that the set of acceptable
    residues at each position is independent of the overall sequence
    context. Two approaches are used to test this assumption. First, highly
    conservative replacements of exterior residues, none of which would
    cause significant functional disruption alone, are combined until
    roughly one in five have been changed. This is found to cause complete
    loss of function in vivo for two unrelated monomeric enzymes: barnase (a
    bacterial RNase) and TEM-1 [beta]-lactamase. Second, a set of hybrid
    sequences is constructed from the 50%-identical TEM-1 and Proteus
    mirabilis [beta]-lactamases. These hybrids match the TEM-1 sequence
    except for a region at the C-terminal end, where they are random
    composites of the two parents. All of these hybrids are biologically
    inactive. In both experiments, complete loss of activity demonstrates
    the importance of sequence context in determining whether substitutions
    are functionally acceptable. Contrary to the prevalent view, then,
    enzyme function places severe constraints on residue identities at
    positions showing evolutionary variability, and at exterior
    non-active-site positions, in particular. Homologues sharing less than
    about two-thirds sequence identity should probably be viewed as distinct
    designs with their own sets of optimizing features."

    This shows that previous estimates of the number of different possible
    sequences that might show a given biological activity, such as H.P.
    Yockey's ("Information theory and molecular biology" (Cambridge:
    Cambridge Univ.Press, 1992), p.254), are likely to be vast overestimates
    because they neglect possible interdependencies between different
    amino-acid positions. I expressed this suspicion in my (unpublished)
    paper at the 1988 Tacoma, WA, conference about Sources of Information
    Content in DNA.

    Peter Ruest <>

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