Caseinolytic protease P (ClpP) (ClpP)

Caseinolytic protease P (ClpP) is a highly conserved serine protease located within the mitochondria of eukaryotic cells and the cytoplasm of most bacteria. It typically assembles into a barrel-shaped tetradecameric complex that works in tandem with AAA+ ATPases, such as ClpX or ClpC, to recognize, unfold, and degrade misfolded or damaged proteins (UniProt, 2024). In the context of drug discovery, ClpP has emerged as a significant target for both oncology and infectious diseases. In cancer, particularly acute myeloid leukemia and glioblastoma, small molecules known as imipridones (e.g., ONC201) allosterically activate human ClpP, triggering an integrated stress response and the degradation of respiratory chain proteins, which leads to tumor cell apoptosis (Ishizawa et al., 2019; PubMed). Conversely, in microbiology, acyldepsipeptides (ADEPs) target bacterial ClpP to cause lethal, non-specific protein degradation, making it a promising target for treating multidrug-resistant infections like Staphylococcus aureus and Mycobacterium tuberculosis (Brotz-Oesterhelt et al., 2005; Nature Medicine).

Other names

ATP-dependent Clp protease proteolytic subunitEndopeptidase ClpMitochondrial Caseinolytic Protease PCLPP

Allosteric activation of the ClpP proteolytic core leads to uncontrolled degradation of essential proteins (in bacteria) or mitochondrial respiratory chain subunits (in humans), resulting in metabolic collapse and cell death. Some inhibitors act by blocking the interaction between ClpP and its cognate AAA+ chaperones (e.g., ClpX or ClpC1).