Unfoldase

Unfoldase is an enzyme that facilitates the unfolding of protein substrates, typically by using energy derived from ATP hydrolysis. Unfoldases play a role in remodeling proteins, disassembling stable complexes, disaggregating misfolded polypeptides, and preparing substrates for proteolytic degradation or refolding. They are commonly associated with the AAA+ ATPase family, which use ring-shaped assemblies to apply mechanical force to substrates.

Mechanistically, unfoldases usually form hexameric or multimeric rings with a central pore through which polypeptide chains are translocated. Substrate recognition is often mediated by adaptor or co-chaperone proteins, and the energy to unfold is provided by ATP binding and hydrolysis. The unfolding process can feed substrates into proteases or chaperone systems, enabling refolding or degradation. Unfoldases frequently work in concert with other chaperones such as Hsp70 to determine whether a substrate is rescued or destroyed.

Major examples include the Hsp70-dependent disaggregases Hsp104 in yeast and its bacterial homolog ClpB, which dissolve protein aggregates. Other unfoldases are ClpC in bacteria, which partners with ClpP for proteolysis, and eukaryotic AAA+ unfoldases such as p97/VCP, which remodels ubiquitinated substrates, and NSF, which disassembles SNARE complexes during vesicle trafficking. These enzymes often function within broader proteostasis networks.

Biological significance includes maintenance of protein homeostasis, prevention of toxic aggregates, and regulation of protein complex dynamics. Unfoldases are studied in the context of neurodegenerative diseases and aging, where protein misfolding is implicated, and they are explored as potential therapeutic targets to modulate proteostasis pathways.