Evolution and Protein Folds

[Keith Robison]

ram at mbisgi.umd.edu (Ram Samudrala) writes:

>Simon Brocklehurst (Bioc) (smb18 at mole.bio.cam.ac.uk) wrote:

>> What you wrote is generally accepted as being correct.  Quite a lot
>>is known about what kind of amino acid substitutions are acceptable in
>>particular structural environments.

>I am now confused as to what you mean by "acceptable".  Who decides
>what is acceptable?  Remember, there's no selection on the protein
>produced by the gene yet.  What's to prevent it from mutating a
>residue in the hydrophobic core to an ASP and thereby destabilising
>the fold by a few Cal? Given that there's no selection on this
>protein, it doesn't seem to matter if it folds up or not.  But it
>does, if it has to evolve to a new function.  Thus there is some
>mechanism that makes sure a compact-fold is preserved.

I think you have answered your own question.  If a protein has the
potential to be functional only if it is folded correctly, than any
genes which have structure-disrupting mutations in them must either
be compensated for by other mutations (or back mutations) or they
are doomed to become pseudogenes.


>What is the mechanism that ensures that no mutations that destroy the
>fold (again, there's really no protein deficiency) are not selected
>for?

To reiterate, there is no need to invoke a special mechanism.
Genes unable to provide a usable structure are unavailable for
further selection; genes which fortuitiously retain a useable 
structural framework can acquire new, selectable functions.

Keith Robison
Harvard University
Department of Cellular and Developmental Biology
Department of Genetics / HHMI

krobison at nucleus.harvard.edu