Genome-wide Interaction Screen for Mycobacterium tuberculosis ClpCP Protease Reveals Toxin- Antitoxin Systems as a Major Substrate Class
Mycobacterium tuberculosis (Mtb) ClpCP is an essential protease and represents an attractive drug target. Researchers from the Weber-Ban group adapted a high-throughput bacterial two-hybrid screen to probe the Mtb proteome leading to the identification of 196 putative interactors, amongst them a large number of toxin-antitoxin complexes.
In Mycobacterium tuberculosis, ClpCP and ClpXP protease complexes mediate essential protein degradation pathways. In recent years, there has been growing interest in ClpC and ClpP as drug targets, prompting the need for a better understanding of their role in protein homeostasis. The Weber-Ban group employed a whole-proteome screen using an adapted bacterial adenylate cyclase two-hybrid system to identify novel protein interaction partners of the ClpC chaperone. They demonstrated that bipartite type II toxin-antitoxin systems present one of the major substrate classes. Further analysis showed that antitoxins could be degraded in vitro by a reconstituted ClpCP complex, implicating the Clp system in M. tuberculosis persistence development. Moreover, it was demonstrated that ClpCP is responsible for mediating the so-called N-end rule that links protein half-lives to the identity of the N-terminal residue.
Link to the paper in external pageThe FEBS Journal