The ATPase VCP/p97 functions as a disaggregase against toxic Huntingtin-exonl aggregates

Intracellular protein aggregation is characterized by accumulation of mis-folded proteins. Chaperones, degradation machineries, and quality-control mechanisms counteract protein aggregation. In this study, we report that the ATPase valosin-containing protein (VCP/p97) acts as a functional disaggregase that disassembles Huntingtin-exonl aggregates in vitro and in HeLa cells. The N-terminal part of VCP (Cdc48_N domain) interacts with the N-terminal 17-amino acid region of Huntingtin-exonl. We show that VCP has properties of a disaggregase, since it is capable of reducing preformed protein aggregates and displays increased ATPase activity in the presence of protein aggregates. However, VCP shows high divergence/disparity from other disaggregases. Taken together, our studies show the novel function of VCP/p97 as a disaggregase which detangles protein aggregates to probably channelize their degradation.