Mycobacterial caseinolytic protease P1P2C1 complex (ClpP1P2C1)

The Mycobacterial caseinolytic protease P1P2C1 complex is a critical multi-component molecular machine essential for maintaining protein homeostasis (proteostasis) in Mycobacterium tuberculosis (Akopian et al., 2012). It consists of a proteolytic core formed by two distinct heptameric rings (ClpP1 and ClpP2) and an associated AAA+ ATPase chaperone, ClpC1, which utilizes ATP energy to unfold and translocate substrate proteins into the protease's central chamber for degradation (Raju et al., 2012). Unlike many other bacteria where Clp proteases are non-essential, both the proteolytic core and the chaperone components are indispensable for the survival and virulence of M. tuberculosis in both growing and dormant states (Gavrish et al., 2014). This essentiality makes the complex a high-priority target for novel anti-tubercular drug development, particularly against multidrug-resistant (MDR) strains (Gao et al., 2015). Pharmacological intervention can take several forms, including the use of lassomycin or ecumicin to inhibit the ClpC1 chaperone, or acyldepsipeptides (ADEPs) to overactivate the ClpP core into an unregulated 'proteolytic monster' that lethally degrades essential cellular proteins (Famulla et al., 2016; Yang et al., 2023).

Other names

ClpP1P2 proteaseMycobacterium tuberculosis ClpP1P2C1 proteaseCaseinolytic protease P1P2C1ClpP1P2-ClpC1 complexClpP1P2-ClpC1 holoenzyme

The complex is targeted through three primary modalities: direct inhibition of the ClpP1P2 proteolytic core which prevents essential protein turnover; dysregulation or hyperactivation of the protease core (by ADEPs) leading to non-selective degradation of nascent and folded proteins; and inhibition or uncoupling of the ClpC1 ATPase chaperone which prevents the recognition and delivery of substrates to the protease.