title: Evolutionary trend toward kinetic stability in the folding trajectory of RNases H.
abstract: Proper folding of proteins is critical to producing the biological machinery essential for cellular function. The rates and energetics of a protein's folding process, which is described by its energy landscape, are encoded in the amino acid sequence. Over the course of evolution, this landscape must be maintained such that the protein folds and remains folded over a biologically relevant time scale. How exactly a protein's energy landscape is maintained or altered throughout evolution is unclear. To study how a protein's energy landscape changed over time, we characterized the folding trajectories of ancestral proteins of the ribonuclease H (RNase H) family using ancestral sequence reconstruction to access the evolutionary history between RNases H from mesophilic and thermophilic bacteria. We found that despite large sequence divergence, the overall folding pathway is conserved over billions of years of evolution. There are robust trends in the rates of protein folding and unfolding; both modern RNases H evolved to be more kinetically stable than their most recent common ancestor. Finally, our study demonstrates how a partially folded intermediate provides a readily adaptable folding landscape by allowing the independent tuning of kinetics and thermodynamics.
authors: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.|Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA 94720.
authors: Shion A
authors: SA
authors: Lim
authors: Department of Chemistry, University of California, Berkeley, CA 94720.
authors: Kathryn M
authors: KM
authors: Hart
authors: Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403.|Institute of Molecular Biology, University of Oregon, Eugene, OR 97403.
authors: Michael J
authors: 0000-0002-0241-4122
authors: MJ
authors: Harms
authors: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; marqusee@berkeley.edu.|Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA 94720.
authors: Susan
authors: S
authors: Marqusee
mesh_terms: D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D019143:Evolution, Molecular; D007700:Kinetics; D010802:Phylogeny; D017510:Protein Folding; D016914:Ribonuclease H / Q000737:chemistry* / Q000235:genetics*; D013816:Thermodynamics; D016963:Thermus thermophilus / Q000201:enzymology / Q000235:genetics
chemical_list: D016914:Ribonuclease H
keywords: ancestral sequence reconstruction; energy landscape; protein evolution; protein folding