Unboxing the treasure chest: tinkering proteins beyond the natural repertoire

Abstract

Proteins are the molecular machineries of life, and engineering them in order to probe and tailor biological function has long remained pure imagination. Cracking the genetic code, the blueprint of proteins, gave the spark to turn precise protein engineering into reality, and even to explore new designer genetic codes. Organisms in all kingdoms of life evolved a highly similar genetic code, which defines how genetic information is translated into proteins. Only a small set of 20 so-called canonical amino acids are used by ribosomes to build proteins. Is the genetic code in this form key to all lives, no matter where in the universe it evolved? Already on Earth we find two powerful exceptions. Selenocysteine represents the 21st canonical amino acid and can even be found in some human proteins. Pyrrolysine is termed the 22nd proteogenic amino acid and has been identified, e.g., in archaeal organisms that grow in anaerobic environments, such as the sludge of a lake or the paunch of a cow. So if one could expand the genetic code even further, proteins could be generated consisting partially or even entirely of artificial amino acid polymers, giving rise to a large diversity of novel natural and unnatural functions. In fact, this future is already present, with genetic code expansion representing a powerful technique which allows to equip proteins with hundreds of non-canonical amino acids, including ones that do not exist in nature. This opens a treasure chest of entirely new protein structures and functionalities. Despite the great potential for biotechnology and medicine, installing a new genetic code, especially in human cells, still bears major challenges. Our laboratory, among others, strives to develop new strategies to expand the genetic code inside of living cells and, at the same time, maintain their native genetic code. Come and join us for this brief journey through the milestones of protein engineering, up to the latest breakthroughs in encoding non-natural chemical properties, and you may get as excited as we are about where protein engineering is heading in the upcoming years.