Molecular chaperones and selection against mutations

Abstract

Abstract Background Molecular chaperones help to restore the native states of proteins after their destabilization by external stress. It has been proposed that another function of chaperones is to maintain the activity of proteins destabilized by mutation, weakening the selection against suboptimal protein variants. This would allow for the accumulation of genetic variation which could then be exposed during environmental perturbation and facilitate rapid adaptation. Results We focus on studies describing interactions of chaperones with mutated polypeptides. There are some examples that chaperones can alleviate the deleterious effects of mutations through increased assistance of destabilized proteins. These experiments are restricted to bacteria and typically involve overexpression of chaperones. In eukaryotes, it was found that the malfunctioning of chaperones aggravated phenotypic aberrations associated with mutations. This effect could not be linked to chaperone-mediated stabilization of mutated proteins. More likely, the insufficient activity of chaperones inflicted a deregulation of multiple cellular systems, including those responsible for signaling and therefore important in development. As to why the assistance of mutated proteins by chaperones seems difficult to demonstrate, we note that chaperone-assisted folding can often co-exist with chaperone-assisted degradation. There is growing evidence that some chaperones, including those dependent on Hsp90, can detect potentially functional but excessively unstable proteins and direct them towards degradation instead of folding. This implies that at least some mutations are exposed rather than masked by the activity of molecular chaperones. Conclusion It is at present impossible to determine whether molecular chaperones are mostly helpers or examiners of mutated proteins because experiments showing either of these roles are very few. Depending on whether assistance or disposal prevails, molecular chaperones could speed up or slow down evolution of protein sequences. Similar uncertainties arise when the concept of chaperones (mostly Hsp90) as general regulators of evolvability is considered. If the two roles of chaperones are antagonistic, then any (even small) modification of the chaperone activities to save mutated polypeptides could lead to increased misfolding and aggregation of other proteins. This would be a permanent burden, different from the stochastic cost arising from indiscriminate buffering of random mutations of which many are maladaptive. Reviewers This article was reviewed by A. S. Kondrashov, J. Höhfeld (nominated by A. Eyre-Walker) and D. A. Drummond (nominated by C. Adami). For the full reviews, please go to the Reviewers' comments section.