Caseinolytic protease P1/P2 complex (ClpP1/P2)

The Caseinolytic protease P1/P2 complex (ClpP1/P2) is an essential, ATP-dependent serine protease system found in Mycobacterium tuberculosis (Mtb). Unlike most bacteria that utilize a single ClpP homooligomer, Mtb requires a heterotetradecameric complex consisting of two distinct heptameric rings, ClpP1 and ClpP2, which must associate to become catalytically active (Akopian et al., 2012, Nature). This complex plays a vital role in bacterial proteostasis by degrading misfolded or damaged proteins, a process necessary for Mtb survival during both active growth and dormant phases of infection (Famulla et al., 2016, Molecular Microbiology). Because ClpP1/P2 is vital for Mtb viability and lacks a direct functional equivalent in the human cytosol, it has become a high-priority target for the development of next-generation antitubercular agents. Small molecules such as acyldepsipeptides (ADEPs) can bind to the complex and cause it to undergo uncontrolled proteolysis, effectively leading to bacterial self-digestion, while other molecules like lassomycin act as potent inhibitors by blocking the interaction with regulatory ATPases (Gavrish et al., 2014, Chemistry & Biology; Chou et al., 2014, JACS).

Other names

ClpP1P2Mycobacterium tuberculosis ClpP1/P2ClpP1-ClpP2 complexCaseinolytic protease PClpP1/2

Dysregulation of proteolytic activity via allosteric activation (leading to uncontrolled degradation) or direct inhibition of the proteolytic core.