Caseinolytic peptidase proteolytic subunit (ClpP) (ClpP)

The Caseinolytic peptidase proteolytic subunit (ClpP) is a highly conserved serine protease located within the mitochondrial matrix of eukaryotic cells and the cytoplasm of bacteria (UniProt Consortium, 2023). It typically functions as a barrel-shaped tetradecamer that, in association with AAA+ chaperones like ClpX, degrades misfolded or damaged proteins to maintain cellular proteostasis (Bhandari et al., 2020). In recent years, ClpP has emerged as a significant therapeutic target in oncology, particularly for acute myeloid leukemia and certain solid tumors, where its overexpression is linked to cancer cell survival (Ishizawa et al., 2019). Small molecule activators, such as the imipridone ONC201, bind to ClpP and induce a constitutively active state that leads to the non-specific degradation of essential mitochondrial enzymes, resulting in mitochondrial collapse and tumor cell apoptosis (Graves et al., 2019). Additionally, ClpP is a validated target for antibacterial drug development, as its hyperactivation by acyldepsipeptides can disrupt bacterial homeostasis and lead to cell death (Wong et al., 2018).

Other names

ATP-dependent Clp protease proteolytic subunitEndopeptidase ClpMitochondrial ClpPCLPPClpP1ClpP2

Small molecule activation of the ClpP protease leads to the uncontrolled degradation of mitochondrial proteins, causing mitochondrial dysfunction and apoptosis (Ishizawa et al., 2019; Graves et al., 2019).