High stability and enhanced promiscuity (likely linked to conformational flexibility/diversity) contribute to evolvability and are advantageous features in protein scaffolds for laboratory directed evolution and molecular design. Furthermore, the two features are not necessarily incompatible and proteins may simultaneously be promiscuous/flexible and highly stable.  In fact, it appears plausible that the combination of the two features was not uncommon among the most ancient proteins because, i) ancient life was likely thermophilic and, ii) ancient proteins were likely promiscuous generalists with broad functionalities. Phylogenetic analyses allow the reconstruction of ancestral sequences and provide and approach to explore the properties of ancient proteins. High stability and promiscuity have been often found for proteins encoded by reconstructed ancestral sequences, i.e. for "resurrected" ancestral proteins. The combination of the two features, i.e. the ancestral hyperstable generalist phenotype, has actually been obtained in recent studies. Ancestral protein resurrection thus emerges as a useful source of scaffolds for protein engineering.

Resurrected ancestral proteins as scaffolds for protein engineering

254th National Meeting (2017)

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