ATP-dependent protease ATP-binding subunit ClpC2 (ClpC2)

ClpC2 is a regulatory protein and partial homologue of the essential AAA+ ATPase ClpC1 found in Mycobacterium tuberculosis and other actinobacteria. Unlike ClpC1, which is a core component of the ClpCP protease complex required for protein degradation, ClpC2 lacks the full ATPase motor domains and primarily functions as a transcriptional repressor and a 'molecular sponge.' Under standard growth conditions, ClpC2 represses its own transcription; however, upon exposure to certain natural antibiotics like Cyclomarin A or Rufomycin, the drug binds to ClpC2 and relieves this repression. This leads to a massive upregulation of ClpC2, which then sequesters the antibiotic molecules to prevent them from inhibiting the essential ClpC1 target, thereby protecting the bacterial proteostasis system. This sequestration mechanism represents a significant therapeutic challenge, as it reduces the effective concentration of Clp-targeting drugs. Recent drug development efforts have focused on using BacPROTACs (Bacterial Proteolysis Targeting Chimeras) to induce the simultaneous degradation of both ClpC1 and its ClpC2 caretaker, effectively bypassing this intrinsic resistance mechanism to kill the pathogen.

Other names

ClpC1 partial homologueClp scavenger proteinClpC2 caretakerClpC2 transcriptional repressor

ClpC2 acts as a molecular sponge by sequestering antibiotics away from the essential ClpC1 target; it also functions as a transcriptional repressor that upregulates itself upon drug binding; BacPROTACs target ClpC2 for degradation to overcome this resistance mechanism.