De novo active sites for resurrected Precambrian enzymes

Valeria A. Risso, Sergio Martinez-Rodriguez, Adela M. Candel, Dennis M. Krüger, David Pantoja-Uceda, Mariano Ortega-Muñoz, Francisco Santoyo-Gonzalez, Eric A. Gaucher, Shina C. L. Kamerlin (), Marta Bruix, Jose A. Gavira and Jose M. Sanchez-Ruiz ()
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Valeria A. Risso: Facultad de Ciencias University of Granada
Sergio Martinez-Rodriguez: Facultad de Ciencias University of Granada
Adela M. Candel: Facultad de Ciencias University of Granada
Dennis M. Krüger: Science for Life Laboratory, Uppsala University
David Pantoja-Uceda: Instituto de Quimica Fisica Rocasolano, CSIC
Mariano Ortega-Muñoz: Facultad de Ciencias University of Granada
Francisco Santoyo-Gonzalez: Facultad de Ciencias University of Granada
Eric A. Gaucher: School of Biology, School of Chemistry and Biochemistry, Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology
Shina C. L. Kamerlin: Science for Life Laboratory, Uppsala University
Marta Bruix: Instituto de Quimica Fisica Rocasolano, CSIC
Jose A. Gavira: Laboratorio de Estudios Cristalograficos, Instituto Andaluz de Ciencias de la Tierra, CSIC-University of Granada Avenida de la Palmeras 4
Jose M. Sanchez-Ruiz: Facultad de Ciencias University of Granada

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Protein engineering studies often suggest the emergence of completely new enzyme functionalities to be highly improbable. However, enzymes likely catalysed many different reactions already in the last universal common ancestor. Mechanisms for the emergence of completely new active sites must therefore either plausibly exist or at least have existed at the primordial protein stage. Here, we use resurrected Precambrian proteins as scaffolds for protein engineering and demonstrate that a new active site can be generated through a single hydrophobic-to-ionizable amino acid replacement that generates a partially buried group with perturbed physico-chemical properties. We provide experimental and computational evidence that conformational flexibility can assist the emergence and subsequent evolution of new active sites by improving substrate and transition-state binding, through the sampling of many potentially productive conformations. Our results suggest a mechanism for the emergence of primordial enzymes and highlight the potential of ancestral reconstruction as a tool for protein engineering.

Date: 2017
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DOI: 10.1038/ncomms16113

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