AAAATPases

AAA ATPases, or AAA+ ATPases, are a large and diverse family of enzymes that use energy from ATP hydrolysis to remodel a wide range of substrates and protein complexes. They act as molecular motors in many cellular processes, including protein quality control, membrane trafficking, DNA transactions, and chromatin remodeling. Commonly found across bacteria, archaea, and eukaryotes, they often function as essential components of larger machines such as proteases, chaperones, or remodeling complexes.

Structurally, most AAA+ ATPases form hexameric rings that create a central pore through which substrates can be threaded and remodelled. Each subunit contains a conserved ATPase core with Walker A and Walker B motifs that bind and hydrolyze ATP. The pore loops, bearing conserved aromatic residues, interact with substrates, enabling mechanically coupled movement. Many AAA+ enzymes also possess additional substrate-recognition domains or regulatory regions, and some subfamilies contain two ATPase domains per subunit (D1 and D2), conferring higher processivity. Subunit exchange and interactions with adaptor or cofactor proteins regulate substrate specificity and activity.

Functionally, AAA+ motors unfold or remodel proteins and complexes, often feeding substrates into proteolytic chambers such as ClpXP, ClpAP, or the 26S proteasome. Others disassemble protein complexes (e.g., NSF for SNAREs), disaggregate aggregated proteins (e.g., ClpB/Hsp104), or remodel chromatin and DNA-associated structures. In eukaryotes, the p97/VCP ATPase participates in diverse pathways with cofactors like Ufd1-Npl4, supporting protein quality control and signaling.

Dysfunction or misregulation of AAA+ ATPases is linked to disease and they are investigated as potential therapeutic targets in infectious diseases and cancer.