Caseinolytic peptidase X (ClpX)

Caseinolytic peptidase X (ClpX) is a highly conserved AAA+ (ATPases Associated with diverse cellular Activities) ATPase that serves as a critical molecular chaperone and regulatory subunit within the ClpXP protease complex (UniProt, 2023). Its primary biological function involves the recognition, unfolding, and translocation of specific protein substrates into the proteolytic chamber of ClpP for degradation (Bhandari et al., 2018). This process is essential for maintaining bacterial proteostasis, managing stress responses, and regulating the cell cycle by degrading key proteins like FtsZ (Sass et al., 2011). In many pathogenic bacteria, such as Staphylococcus aureus and Mycobacterium tuberculosis, ClpX is indispensable for survival and virulence, making it an attractive target for the development of next-generation antibiotics (Gao et al., 2015). Pharmacological modulation of ClpX typically involves either the inhibition of its ATPase-driven unfolding activity or the disruption of its interaction with ClpP, which can lead to the accumulation of toxic protein aggregates or uncontrolled proteolysis (Brötz-Oesterhelt & Sass, 2014). While ClpX presents a high-value target for treating multi-drug resistant infections, drug design must ensure selectivity to avoid interfering with the human mitochondrial homolog, hClpX, which could lead to host toxicity (Kurat et al., 2017).

Other names

ATP-dependent Clp protease ATP-binding subunit ClpXClpX chaperoneAAA+ ATPase ClpXCaseinolytic protease X

Inhibition of ATPase activity and protein unfolding, or disruption of the ClpXP protease complex assembly to prevent regulated protein degradation; alternatively, some drugs (ADEPs) bind the associated ClpP core to displace ClpX and cause dysregulated proteolysis.