ClpC

ClpC is an ATP-dependent chaperone protein in bacteria that belongs to the AAA+ (ATPases Associated with various Activities) family. It functions as part of a proteolytic machine by partnering with the ClpP protease to recognize, unfold, and degrade targeted substrates, contributing to protein quality control and regulatory pathways.

Structurally, ClpC forms a hexameric ring composed of two nucleotide-binding domains (NBD1 and NBD2) and an N-terminal substrate-recognition domain. This arrangement enables energy-driven remodeling of substrate proteins. Substrate selection is guided by adaptor proteins, which recruit specific targets to the ClpC-ClpP protease core. In Bacillus and related Gram-positive bacteria, adaptors such as MecA and the McsB/McsA module help direct regulatory and stress-related substrates to ClpC for degradation.

Functionally, ClpC participates in both housekeeping and stress responses. It degrades misfolded or damaged proteins and regulates developmental processes by targeting key regulatory proteins for turnover. For example, in Bacillus species, adaptors mediate degradation of competence regulators and other factors, linking ClpC activity to outcomes such as competence, sporulation, and stress adaptation. The proteolytic activity is context-dependent, with adaptor availability determining which substrates are processed.

Distribution and regulation vary among species. ClpC is widespread in Gram-positive bacteria and is sometimes present alongside distinct ClpP isoforms or additional adaptor networks that tailor substrate specificity. Expression and activity are often upregulated in response to cellular stress, enabling rapid remodeling of the proteome.

ClpC is of interest in antimicrobial research as a potential target to disrupt bacterial proteostasis. Inhibiting ClpC function can impair stress tolerance and virulence in certain pathogens, offering a route for novel therapeutic strategies.