unfoldases

Unfoldases are molecular machines that use energy from ATP hydrolysis to unfold protein substrates or remodel protein complexes. They are typically members of the AAA+ (ATPases associated with diverse cellular activities) superfamily and often form hexameric rings with a central pore through which polypeptide chains are threaded. Substrate engagement occurs at the pore entrance, and conformational changes driven by ATP binding and hydrolysis translocate the polypeptide, effectively unfolding it and preparing it for proteolysis or disassembly of protein assemblies.

In bacteria, unfoldases such as ClpX and ClpA partner with proteolytic cores (for example, ClpP) to degrade targeted substrates. Adaptor proteins help specify substrates. ClpB, another AAA+ member, functions primarily as a disaggregase that solubilizes and remodels aggregated proteins, supplying unfolded chains to the proteolytic system in some contexts.

In eukaryotes, unfoldase activity is exemplified by p97/VCP (also known as Cdc48 in some organisms), a cytosolic/nuclear AAA+ ATPase that extracts ubiquitinated substrates from protein complexes or membranes for delivery to the proteasome. Cofactors such as Ufd1-Npl4 assist substrate recognition. The proteasome itself possesses unfoldase activity within its 19S regulatory particle, where the AAA+ Rpt1–Rpt6 subunits couple substrate unfolding to translocation into the proteolytic core.

Functions of unfoldases include protein quality control, regulated proteolysis, extraction of misfolded or regulatory subunits from membranes or complexes, and remodeling of macromolecular assemblies during various cellular processes, such as DNA replication and vesicle trafficking.

Clinical and research relevance arises from the central role of unfoldases in proteostasis; defects or dysregulation of unfoldases like p97/VCP are linked to multisystem disorders and neurodegenerative conditions, highlighting their importance in health and disease.