Mycobacterium tuberculosis ClpP1P2 caseinolytic protease complex (ClpP1P2)

The Mycobacterium tuberculosis ClpP1P2 caseinolytic protease complex is a vital multi-subunit enzyme responsible for maintaining protein homeostasis by degrading misfolded or damaged proteins (Akopian et al., 2012, PubMed: 22503490). It is uniquely composed of two distinct heptameric rings, ClpP1 and ClpP2, which must associate to form the active tetradecameric proteolytic core (UniProt P9WPC5; UniProt P9WPC3). This complex functions in tandem with AAA+ ATPases, such as ClpC1, which act as gatekeepers to unfold and feed substrates into the ClpP1P2 chamber (Schmitt et al., 2011, PubMed: 21835174). Because the complex is essential for the survival and pathogenesis of M. tuberculosis, it is a high-priority target for the development of new antitubercular agents (Raju et al., 2012, PubMed: 22952924). Pharmacological intervention typically involves either inhibiting the protease activity to cause toxic protein accumulation or dysregulating the complex with acyldepsipeptides (ADEPs) to trigger uncontrolled degradation of essential cellular components (Ollinger et al., 2012, PubMed: 22431991). The structural differences between the mycobacterial ClpP1P2 complex and the human mitochondrial ClpP provide a basis for achieving therapeutic selectivity (Compain et al., 2018, PubMed: 30033734).

Other names

ClpP1P2 complexMtb ClpP1P2Caseinolytic protease P1/P2ClpP1P2 heterotetradecamer

Small molecules target the ClpP1P2 complex either by inhibiting its proteolytic activity, thereby preventing the degradation of regulatory and misfolded proteins, or by dysregulating the gate-opening mechanism to induce uncontrolled proteolysis of essential proteins (Ollinger et al., 2012, PubMed: 22431991).