ClpX

ClpX is an essential ATP-dependent chaperone that forms part of the ClpXP protease complex in bacteria and is present in some organelles such as mitochondria. It belongs to the AAA+ (ATPases associated with diverse cellular activities) family and functions as the unfoldase that recognizes, unfolds, and translocates substrate proteins into the ClpP proteolytic core for degradation. Through this activity, ClpX contributes to protein quality control, regulation of cellular processes, and stress responses by removing damaged, misfolded, or regulatory proteins.

Structure and mechanism: ClpX typically forms a homo-hexameric ring. Each subunit contains an N-terminal domain involved in substrate recognition and a C-terminal AAA+ domain containing the Walker A and Walker B motifs that bind and hydrolyze ATP. Substrate engagement occurs at the central pore of the hexamer, where pore loops translocate the unfolded polypeptide into ClpP. ClpX interacts with ClpP via a conserved docking motif (IGF loop) that inserts into a hydrophobic pocket on ClpP to stimulate proteolysis. Substrates are often marked by degrons or degron-adaptor proteins that help recruit them to ClpX.

Biological roles: In Escherichia coli and many other bacteria, ClpXP degrades a range of substrates including misfolded proteins and particular regulatory proteins, thereby influencing stress responses, cell cycle control, and adaptation to environmental changes. Adaptor proteins and degrons expand substrate specificity, enabling targeted proteolysis. In mitochondria and chloroplasts, ClpX homologs participate in maintaining organellar proteostasis in concert with ClpP.

Distribution and significance: ClpX is widely conserved among bacteria and in plant and fungal organelles, reflecting its central role in maintaining cellular protein homeostasis and regulated proteolysis.