New covalent bridge found in proteins

Researchers have found a new type of cross-link between amino acids in a protein (Nature 2021, DOI: 10.1038/s41586-021-03513-3). The intramolecular linkage is an N-O-S bridge formed by oxidizing the amine side group of a lysine and the thiol of a cysteine residue.

The team that made the discovery, led by Kai Tittmann at the Georg August University Göttingen, was investigating an enzyme from Neisseria gonorrhoeae called a transaldolase. When they made the protein in the lab, they found it was not active unless subjected to a reducing agent. That is usually evidence of a bridge between neighboring cysteine residues. The researchers combined data from X-ray crystallography and mutation experiments and soon realized the bridge in their enzyme is different. The covalent bond is formed by an oxygen atom that sits between the nitrogen of one amino acid and the sulfur of another and acts like a redox-activated switch for the enzyme. When oxidized, the bridge changes the protein’s shape sufficiently so that it is not catalytically active. Adding a reducing agent breaks the bridging bond, and the protein becomes active once more. Although the exact chemical mechanism for forming the N-O-S bridge is unknown at this time, the researchers looked at other protein structures in the Protein Data Bank and found evidence that their enzyme is not the only protein structure that has this previously unknown feature. How widespread the new linkage is is also unsolved so far.