Scientists ‘resurrect’ ancient proteins to provide clues about molecular innovation

Picture of ID23-1, one of the ESRF structural biology beamlines where the experiments were carried out. Credit: ESRF/P. Jayet

Enzyme activity is determined by the structure of a particular region of a protein called the active site. The generation of completely new active sites capable of enzyme catalysis is, arguably, one of the most fundamental unsolved problems in molecular biology.

Rational and modern design approaches to this problem have been developed using complex computational methods, but without conclusive results. Indeed, protein engineering studies often suggest that the emergence of completely new enzyme active sites is highly improbable.

Many years ago, Roy Jensen (currently at the University of Kansas Medical Center) proposed that primordial enzymes were capable of catalyzing a diversity of reactions. Based on this work, a multi-institutional collaborative of scientists explored and tested these notions using resurrected Precambrian β-lactamases as scaffolds for the engineering of completely new active sites. Precambrian β-lactamases are proteins approximately 3 billion years old. Basically, the scientists brought these ancient proteins back to life so that they can be studied to better understand how complexity in species arises.

How is it possible to resurrect ancestral proteins? Proteins are made from various combinations of amino acid building blocks, with a nearly endless variety of complexity and function. Researchers have compiled large databases of protein sequences. By comparing today’s sequences to each other within an evolutionary framework, scientists can reasonably infer the sequence of an ancestral protein from which the modern versions descended using models of sequence evolution.

“The properties of these ancestral proteins (Precambrian…

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