期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：13045-13050
DOI：10.1073/pnas.1611781113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceBecause protein folding is crucial to proper cellular function, there must be evolutionary pressures on how a protein achieves and maintains its folded structure. The outcome of these pressures on a folding pathway should be reflected in trends and patterns over a proteins evolutionary history. To understand how folding pathways evolve, we characterized how reconstructed ancestral proteins of the ribonuclease H family fold. The deepest ancestors fold and unfold faster than their modern descendants, and kinetic stability evolved along both mesophilic and thermophilic lineages. This trend is possible because of a conserved partially folded intermediate state, which uncouples thermodynamic and kinetic stability to allow each parameter to evolve independently. Proper folding of proteins is critical to producing the biological machinery essential for cellular function. The rates and energetics of a proteins 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 proteins energy landscape is maintained or altered throughout evolution is unclear. To study how a proteins 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.
关键词：protein folding ; energy landscape ; protein evolution ; ancestral sequence reconstruction
