Chemical chaperones assist intracellular folding to buffer mutational variations

Area of Science:

• Biochemistry
• Molecular Biology
• Evolutionary Genetics

Background:

• Genetic variations can lead to new traits, but their effects may be hidden.
• Molecular chaperones assist protein folding and can conceal genetic variations.
• The cellular chemical environment (milieu) might influence protein folding and mask mutations.

Purpose of the Study:

• Investigate if the cellular chemical milieu can alleviate intracellular protein folding issues.
• Explore the role of osmolytes in concealing genetic variations.
• Determine if osmolytes can buffer mutations impacting protein folding pathways.

Main Methods:

• Utilized the model osmolyte trimethylamine N-oxide (TMAO) to test its effect on protein folding.
• Examined two model proteins to assess TMAO's buffering capacity on mutations.
• Designed and studied TMAO-dependent mutants in vivo, starting from a TMAO-independent protein.

Main Results:

• Trimethylamine N-oxide (TMAO) was found to buffer mutations that create kinetic traps in protein folding pathways.
• Different osmolytes exhibit unique capabilities in buffering specific sets of mutations.
• Cellular chemical environments can modify folding pathways of mutant variants in populations.

Conclusions:

• The cellular chemical milieu plays a significant role in modulating the effects of genetic variations.
• Osmoytes can buffer specific mutations, potentially influencing evolutionary trajectories.
• Cellular chemistry contributes to genetic buffering, leading to diverse outcomes in polymorphic populations.