Soluble oligomerization provides a beneficial fitness effect on destabilizing mutations.


Abstract

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.

Submission Details

ID: zYeWZok24

Submitter: Shu-Ching Ou

Submission Date: July 30, 2018, 1:59 p.m.

Version: 1

Publication Details
Bershtein S;Mu W;Shakhnovich EI,Proc Natl Acad Sci U S A (2012) Soluble oligomerization provides a beneficial fitness effect on destabilizing mutations. PMID:22411825
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