title: Chemical chaperones assist intracellular folding to buffer mutational variations.
abstract: Hidden genetic variations have the potential to lead to the evolution of new traits. Molecular chaperones, which assist protein folding, may conceal genetic variations in protein-coding regions. Here we investigate whether the chemical milieu of cells has the potential to alleviate intracellular protein folding, a possibility that could implicate osmolytes in concealing genetic variations. We found that the model osmolyte trimethylamine N-oxide (TMAO) can buffer mutations that impose kinetic traps in the folding pathways of two model proteins. Using this information, we rationally designed TMAO-dependent mutants in vivo, starting from a TMAO-independent protein. We show that different osmolytes buffer a unique spectrum of mutations. Consequently, the chemical milieu of cells may alter the folding pathways of unique mutant variants in polymorphic populations and lead to unanticipated spectra of genetic buffering.
authors.affiliation: Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: Anannya
authors.initials: A
authors.lastname: Bandyopadhyay
authors.forename: Kanika
authors.initials: K
authors.lastname: Saxena
authors.forename: Neha
authors.initials: N
authors.lastname: Kasturia
authors.forename: Vijit
authors.initials: V
authors.lastname: Dalal
authors.forename: Niraj
authors.initials: N
authors.lastname: Bhatt
authors.forename: Asher
authors.initials: A
authors.lastname: Rajkumar
authors.forename: Shuvadeep
authors.initials: S
authors.lastname: Maity
authors.forename: Shantanu
authors.initials: S
authors.lastname: Sengupta
authors.forename: Kausik
authors.initials: K
authors.lastname: Chakraborty
mesh_terms: D007700:Kinetics; D058619:Maltose-Binding Proteins / Q000737:chemistry* / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D008744:Methylamines / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017510:Protein Folding / Q000187:drug effects*
chemical_list: D058619:Maltose-Binding Proteins; D008744:Methylamines; C005855:trimethyloxamine