The ATPase VCP/p97 functions as a disaggregase against toxic Huntingtin‐exon1 aggregates

Abstract

Intracellular protein aggregation is characterized by accumulation of misfolded 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-exon1 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-exon1. 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.

HYPK scaffolds the Nedd8 and LC3 proteins to initiate formation of autophagosome around polyneddylated huntingtin exon1 aggregates

“…The cladogram was generated in the Treeview software. The process of phylogenetic analysis followed the same set of steps as described in our previous study ( 47 ).…”

Golgi Structure and Function in Health, Stress, and Diseases

“…-Thyroid receptor (Chen et al 1999) • Golgi ribbon formation (Rios et al 2004) • Membrane tethering (Drin et al 2008) • ER-to-Golgi trafficking (Gillingham et al 2004) • γ-tubulin recruitment (Rios et al 2004) • Sorting to primary cilia (Follit et al 2008) • Interacts with thyroid hormone receptor beta (Chen et al 1999 • Membrane reassembly (Kondo et al 1997;Ramadan et al 2007;Hetzer et al 2001) • Cell cycle progression (Cao et al 2003;Fu et al 2003;Parisi et al 2018) • Protein aggregation (Ghosh et al 2018;Ristic et al 2018;Yi and Yuan 2017;Kobayashi et al 2007;Song et al 2007;Nishikori et al 2008) • Autophagy (Papadopoulos et al 2017) • DNA repair (Van Den Boom et al 2016;…”

T54R mutation destabilizes the dimer of superoxide dismutase 1T54R by inducing steric clashes at the dimer interface

“…In general, the process of recombinant protein expression and purication was similar to method that was described in our earlier studies. 55,56 Immunoblotting Immunoblotting of recombinant SOD1 and SOD1 T54R proteins was done to analyze the oligomerization status of SOD1 and SOD1 T54R . 40 mg of SOD1 and SOD1 T54R proteins were separated in a native (nondenaturing) PAGE, followed by transfer of proteins from the gel to PVDF membrane.…”