Soluble oligomerization provides a beneficial fitness effect on destabilizing mutations

By S. Bershtein, W. Mu, Eugene I. Shakhnovich. 2011

106 citations recorded by the source corpus.

Mutations create the genetic diversity on which selective pressures can act, yet also create structural instability in proteins. How, then, is it possible for organisms to ameliorate mutation-induced perturbations of protein stability while maintaining biological fitness and gaining a selective advantage? Here we used site-specific chromosomal mutagenesis to introduce a selected set of mostly destabilizing mutations into folA—an essential chromosomal gene of Escherichia coli encoding dihydrofolate reductase (DHFR)—to determine how changes in protein stability, activity, and abundance affect fitness. In total, 27 E. coli strains carrying mutant DHFR were created. We found no significant correlation between protein stability and its catalytic activity nor between catalytic activity and fitness in a limited range of variation of catalytic activity observed in mutants. The stability of these mutants is strongly correlated with their intracellular abundance, suggesting that protein homeostatic machinery plays an active role in maintaining intracellular concentrations of proteins. Fitness also shows a significant correlation with intracellular abundance of soluble DHFR in cells growing at 30 °C. At 42 °C, the picture was mixed, yet remarkable: A few strains carrying mutant DHFR proteins aggregated, rendering them nonviable, but, intriguingly, the majority exhibited fitness higher than wild type. We found that mutational destabilization of DHFR proteins in E. coli is counterbalanced at 42 °C by their soluble oligomerization, thereby restoring structural stability and protecting against aggregation.

Subfields: Genetics, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

In Molecular Biology

Citations in the corpus

A Comprehensive, High-Resolution Map of a Gene’s Fitness Landscape (2014, background): “41 at 37 C), organismal fitness changed very little with protein abundance (Bershtein et al. 2012).”
Merging molecular mechanism and evolution: theory and computation at the interface of biophysics and evolutionary population genetics (2014, background): “The latter can be evaluated either from competition assays or direct measurements of growth rates [10 ,74] or through deep sequencing approaches [76–78].”