A Brand-new Long-term Neglected Protein Switch Found

Posted by Jerry Carter on June 1st, 2021

Proteins play a wide range of functions in the cells of every organism and play a key role in almost every biological process. They are not only responsible for our metabolism, manage cell signaling, and are responsible for energy production, as antibodies, they are also frontline workers of our immune system against human pathogens such as coronaviruses. Given these important responsibilities, it is not surprising that the activity of proteins is tightly controlled.

They have many chemical switches that control the structure of proteins and the response function under changing environmental conditions and stresses. The biochemical structure and mode of operation of these switches are considered to be well understood. However, a group of scientists at the University of Gorgentin, Germany, were surprised to discover a completely new, but until now neglected switch, which appears to be a ubiquitous regulatory element that covers all fields of proteins.

Published in Nature, the researchers investigated a protein (transaldolase) from the human pathogen Neisseria gonorhoae, which causes gonorrhea, a bacterial infection that has more than 100 million cases worldwide. This disease is usually treated with antibiotics, but the increasing rate of antibiotic resistance poses a serious threat. To identify new treatments, they studied the structure and mechanism of a protein that plays a key role in carbon metabolism in pathogens.

Surprisingly, the protein can be switched on and off by oxidation and reduction (called a "redox switch"). Scientists suspect that this is caused by a common, well-established "disulfide switch" formed between the two cysteine amino acids. When they deciphered the X-ray structure of this protein in the “on” and “off” states at the DESY particle accelerator in Hamburg, Germany, they harvested greater surprise. The chemical nature of this switch is completely unknown: it is formed between lysine and cysteine amino acids with a bridging oxygen atom.

“I can't believe my eyes,” said Professor Kai Tittmann, who led the study, recalling the first time he saw the structure of this novel switch. “We initially thought this must be a by-product of the experimental process because this chemical entity is unknown. But multiple repeated experiments always get the same results, and analysis of protein structure databases further reveals that there are many other proteins that are likely to have this switch, which clearly escapes early detection because protein structure analysis is not sufficiently resolved to detect it.” The researchers acknowledge that luck is on their side because the crystals they measure are able to determine protein structure with extremely high resolution, which leads to this novel switch that cannot eventually be missed.

Marie Wensien, lead author of the paper, said: “I am so pleased that extensive screening of high-quality protein crystals has indeed paid off.” The researchers believe that the discovery of new protein switches will impact life sciences in many ways, for example, in the field of protein design. It will also open new avenues for medical applications and drug design. Many human proteins with established roles in severe diseases are thought to be redox-controlled, and the newly identified switches may also play a central role in regulating their biological functions.