ATP-dependent Clp protease proteolytic subunit (ClpP)

ATP-dependent Clp protease proteolytic subunit (ClpP) is a highly conserved serine protease found in bacteria and the mitochondria of eukaryotic cells. It forms a cylindrical tetradecameric (14-mer) complex that degrades misfolded or damaged proteins, collaborating with AAA+ ATPase chaperones (e.g., ClpX, ClpA, ClpC) that target and unfold substrates for translocation into ClpP’s proteolytic chamber. In bacteria, ClpP is essential for adaptation to stress, virulence, and cell survival, making it a promising antimicrobial drug target. In humans, mitochondrial ClpP helps maintain mitochondrial protein quality, with mutations linked to Perrault syndrome (characterized by hearing loss and ovarian abnormalities). Pharmacological modulation of ClpP (activation or inhibition) can result in bacterial death or impaired mitochondrial function, and several small-molecule modulators are under active study as antibacterials and anticancer agents. ClpP is a member of the S14 peptidase family, uses an internal serine-histidine-aspartate catalytic triad for peptide bond hydrolysis, and is assembled as a barrel with its active sites sequestered within the chamber. Its function and regulation are critical both for cellular adaptation and as an emerging therapeutic target in infection and potentially cancer.

Other names

Caseinolytic protease proteolytic subunitEndopeptidase ClpCLPP

ClpP activators (ADEPs, ONC201): cause uncontrolled proteolysis leading to cell death. ClpP inhibitors (β-lactones): block proteolytic activity, preventing protein turnover and bacterial adaptation.