Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes

Int J Mol Sci. 2021 Jul 28;22(15):8079. doi: 10.3390/ijms22158079.


IBMPFD/ALS is a genetic disorder caused by a single amino acid mutation on the p97 ATPase, promoting ATPase activity and cofactor dysregulation. The disease mechanism underlying p97 ATPase malfunction remains unclear. To understand how the mutation alters the ATPase regulation, we assembled a full-length p97R155H with its p47 cofactor and first visualized their structures using single-particle cryo-EM. More than one-third of the population was the dodecameric form. Nucleotide presence dissociates the dodecamer into two hexamers for its highly elevated function. The N-domains of the p97R155H mutant all show up configurations in ADP- or ATPγS-bound states. Our functional and structural analyses showed that the p47 binding is likely to impact the p97R155H ATPase activities via changing the conformations of arginine fingers. These functional and structural analyses underline the ATPase dysregulation with the miscommunication between the functional modules of the p97R155H.

Keywords: IBMPFD; arginine finger; p47 cofactor; p97 ATPase; p97R155H mutation; single-particle cryo-EM.

MeSH terms

  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism*
  • Humans
  • Microscopy, Electron, Transmission
  • Models, Molecular*
  • Muscular Dystrophies, Limb-Girdle / genetics
  • Muscular Dystrophies, Limb-Girdle / metabolism*
  • Mutation*
  • Myositis, Inclusion Body / genetics
  • Myositis, Inclusion Body / metabolism*
  • Osteitis Deformans / genetics
  • Osteitis Deformans / metabolism*
  • Protein Conformation
  • Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / metabolism*
  • Valosin Containing Protein / genetics*
  • Valosin Containing Protein / metabolism


  • Nsfl1c protein, rat
  • Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins
  • VCP protein, human
  • Valosin Containing Protein

Supplementary concepts

  • Inclusion Body Myopathy With Early-Onset Paget Disease And Frontotemporal Dementia