Protein Regulation Mechanism Discovered

Researchers at the University of Göttingen recently discovered a novel, on/off switch that seems to be a ubiquitous regulatory element in proteins. The results were published today in Nature.

The researchers investigated a protein from the human pathogen Neisseria gonorrhoeae. This disease is typically treated with antibiotics but increasing rates of antibiotic resistance pose a serious threat. In order to identify new treatments, they studied the structure and mechanism of a protein that is a key player in carbon metabolism of the pathogen. Surprisingly, the protein can be switched on and off by oxidation and reduction—known as a redox switch. The scientists suspected this was caused by a common and well-established disulfide switch formed between two cysteine amino acids. When they deciphered the X-ray structures of the protein in the "on" and "off" state at the DESY particle accelerator in Hamburg, Germany, they were hit by an even bigger surprise. The chemical nature of the switch was unknown: it is formed between a lysine and a cysteine amino acid with a bridging oxygen atom.

"I couldn't believe my eyes," says lead researcher Kai Tittmann, who led the study, when he remembers seeing the structure of the novel switch for the first time. "We thought initially that this must have formed artificially as a by-product of the experimental process as this chemical entity was unknown." However, numerous repetitions of the experiments always gave the same result and an analysis of the protein structure database further disclosed that there are many other proteins that very likely possess this switch, which apparently escaped earlier detection as the resolution of the protein structure analysis was insufficient to detect it for certain. The researchers admit that good fortune was on their side because the crystals they measured allowed the protein structure to be determined at extremely high resolution, meaning the novel switch couldn't be missed. "The extensive screening for high-quality protein crystals has really paid off, I couldn't be happier," says Marie Wensien, first author.

The researchers believe the discovert could open new avenues in medical applications and drug design. Many human proteins with established roles in severe diseases are known to be redox-controlled and the newly discovered switch is likely to play a central role in regulating their biological function as well.