Research Allosteric control of the bacterial ClpC/ClpP protease and its hijacking by antibacterial peptides

In Gram-positive bacteria the ATPase ClpC and the peptidase ClpP form a central ATP-dependent protease crucial for stress resistance and virulence. The proteolytic activity of the ClpC/ClpP machine must be tightly regulated to prevent deleterious uncontrolled protein degradation. The Mogk lab in cooperation with Dr. Marta Carroni at SciLifeLab Stockholm used biochemistry and structural biology to determine how ClpC activity is controlled by substrates and partner proteins. They show that ClpC can adopt diverse assembly states including an inactive resting state. Binding of partners or substrates to structural elements needed for resting state formation triggers ClpC activation. Antimycobacterial cyclic peptides hijack this regulatory mechanism, leading to toxicity through uncontrolled proteolysis.