Abstract
Literature from the past two decades has outlined the existence of a trade-off between protein stability and function. This trade-off creates a unique challenge for protein engineers who seek to introduce new functionality to proteins. These engineers must carefully balance the mutation-mediated creation and/or optimization of function with the destabilizing effect of those mutations. Subsequent research has shown that protein stability is positively correlated with “evolvability” or the ability to support mutations which bestow new functionality on the protein. Since the ultimate goal of protein engineering is to create and/or optimize a protein’s function, highly stable proteins are preferred as potential scaffolds for protein engineering. This review focuses on the application potential for thermophilic proteins as scaffolds for protein engineering. The relatively high inherent thermostability of these proteins grants them a great deal of mutational robustness, making them promising scaffolds for various protein engineering applications. Comparative studies on the evolvability of thermophilic and mesophilic proteins have strongly supported the argument that thermophilic proteins are more evolvable than mesophilic proteins. These findings indicate that thermophilic proteins may represent the scaffold of choice for protein engineering in the future.
Highlights
The field of protein engineering focuses on rational modification or combinatorial design of proteins to enhance or otherwise alter protein functionality [1]
Decades of research has shown that there is a negative correlation between protein stability and function; since one of the primary purposes of protein engineering is to create or optimize protein activity, protein engineers face the challenge of maintaining protein stability at the cost of desired functionality
Since thermophilic proteins generally exhibit a higher level of mutational robustness when compared with their mesophilic counterparts, it stands to reason that these proteins are natural candidates to become scaffolds for evolutionary engineering
Summary
The field of protein engineering focuses on rational modification or combinatorial design of proteins to enhance or otherwise alter protein functionality [1]. The present article overviews the research that has been performed on thermophilic proteins as potential scaffolds for protein engineering It reviews research which has defined the trade-off between protein activity and stability, and highlights the challenge this trade-off poses to the field of protein engineering. It discusses research describing how protein stability and mutational robustness directly promote evolvability. It proceeds to introduce thermophilic proteins to this discussion and outline the structural characteristics of these proteins that contribute to their increased stability and mutational robustness It highlights recent research which has utilized highly thermostable proteins as effective scaffolds for engineered functional evolution and, when possible, compares the evolvability of these proteins with that of their mesophilic analogues
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