Periodic Reporting for period 3 - pArg_deg_signal (No stress with pArg: Mechanisms of a distinct phospho-mark to coordinate stress response and protein quality control)
Reporting period: 2019-10-01 to 2021-03-31
The proposed experimental program is of high medical interest, particularly in terms of antibiotics development. New avenues in anti-bacterial therapy are badly needed as bacterial infections are still a leading cause of death worldwide, while the resistance to antibiotics is on the rise. The most worrying gram-positive pathogens including Staphylococcus aureus are characterized by their ability to deal with stress situations imposed by the host defense system. Components of the stress-response regulon such as McsB, ClpC and ClpP are essential for this capability, with ClpP being the target of the powerful acyldepsipeptide antibiotic. Thus, the mechanistic and structural peculiarities of McsB and ClpC that will be revealed by our work, as well as the expected insights into the bacterial version of the ubiquitin-proteasome system, open exciting possibilities in combating some of the most dangerous bacterial pathogens.
One possible site of intervention is the “death-marking” kinase McsB. Fitting to the Latin phrase "Quis custodiet ipsos custodes?" ("Who watches the watchmen?"), most cellular processes are controlled by proteins, but what controls proteins themselves? This task is in part performed by protein kinases, which attach a small chemical unit called phosphoryl group to other proteins. Most protein kinases, promoting this “phosphorylation”, are similar to each other and stem from the same ancestral gene. Our group, however, unraveled the atomic structure of the protein kinase McsB that differs from all other protein kinases in structure and function. As such and owing to the critical role of McsB for bacterial infection, the reported findings may aid developing novel antibiotics. What is special about McsB is that, whereas other protein kinases modify the amino acids serine, threonine, and tyrosine, McsB acts specifically on the amino acid arginine, changing it to pArg. This seemingly small difference results in completely novel signaling pathways connected with a phospho mark. Importantly, pArg residues can be recognized by specific protein domains, three of which are located on ClpC, McsB and CtsR, respectively. The various pArg-reader domains identified by us point to a remarkably complex signaling system – which challenges simpler views of bacterial protein phosphorylation that was formerly believed to be based on isolated kinase modules rather than on phospho-protein networking.