Uma sequência mais uma mutação é igual a duas dobras

One sequence plus one mutation equals two folds

David Shortle

Department of Biological Chemistry, Physiology Building, Room 513, Johns Hopkins University School of Medicine, 725 North Wolfe
Street, Baltimore, MD 21205

In this issue of PNAS, Alexander et al. (1) report an observation that will be a topic of heated discussion among biochemists for a long time to come. A single amino acid substitution can, in the right context, completely change the fold of a protein. And the structural change produced by this one mutation cannot be dismissed as a semantic issue over what constitutes a different fold. As shown in Fig. 1, one conformation consists of a three-helix bundle, whereas the alternate form has a four-strand beta-sheet with a single alpha-helix. Eighty-five percent of residues change their secondary structure, with only eight residues in the central alpha-helix plus one or two turn residues retaining the same conformation in both forms. When I first heard this result in a public seminar, my mind literally began to reel, leaving me dizzy and slightly nauseated as all hope of understanding how sequence encodes structure seemed to suddenly vanish.....

Because we now live in a world where one amino acid sequence plus one mutation actually can give rise to two very different protein folds, what are the implications? How can we make sense of this observation by putting it into the context of our current understanding of the physical chemistry used by protein sequences to encode structure? And what are its implications for the evolution of protein structure over biological time? Should we expect more examples of dramatic protein fold switching, or is there something exceptional about these two protein domains that diminishes the generality of conclusions we might wish to draw? First of all, it comes as no surprise that the sequence of a protein can be extensively modified with little or no appreciable effect on structure. Using selection schemes to recover stably folded proteins from mutagenized libraries, it is often possible to substitute 50% or more of residues without changing the fold or greatly lowering the stability !
(3). Even the kinetics of folding may be little changed from the wild-type values. As one might expect, in such cases most mutant sites are located on the protein surface, where the strength and specificity of interactions are often low. The expected result on going to levels of substitution much higher than 50% would have been destabilization of the folded states, causing much of the sequence pathway connecting the two conformations to be fully unfolded/denatured. But this is not what happened.....

The pattern that emerges for analysis of proteins that switch their conformations is that, given the right amino acid sequence, the ends can convert between alternative structural states, one of which is stabilized by a large number of new contacts.....

For those of us who hope some day to explain the physical chemistry underlying structural phenomena such as shown in Fig. 1, there is some small consolation in the view that more is involved here than the effects of a single side chain. Nevertheless, this paper by Alexander et al. (1) throws into bold relief just how great a challenge remains for developing a complete quantitative understanding of protein structures and their transitions.

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