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Multisystem Proteinopathy Mutations in VCP/p97 Increase NPLOC4·UFD1L Binding and Substrate Processing.

Emily E Blythe1, Stephanie N Gates2, Raymond J Deshaies3

  • 1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Department of Molecular & Cell Biology, University of California, Berkeley, CA 94720, USA.

Structure (London, England : 1993)
|October 19, 2019
PubMed
Summary
This summary is machine-generated.

Mutations in valosin-containing protein (VCP)/p97 cause multisystem proteinopathy (MSP). MSP mutants exhibit enhanced protein unfolding and substrate processing, suggesting a gain-of-function mechanism.

Keywords:
AAA+ ATPaseATP-dependent protein unfoldingUfd1-Npl4VCPmultisystem proteinopathyp97

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Medicine

Background:

  • Valosin-containing protein (VCP)/p97 is a crucial ATP-dependent protein unfoldase.
  • Dominant mutations in p97 lead to multisystem proteinopathy (MSP), impacting brain, muscle, and bone.
  • Molecular defects underlying MSP pathogenesis remain incompletely understood.

Purpose of the Study:

  • To investigate the impact of MSP mutations on p97's unfoldase activity.
  • To elucidate the molecular mechanisms of p97 dysfunction in MSP.
  • To explore p97-adaptor interactions using structural and biochemical methods.

Main Methods:

  • Biochemical assays to measure unfoldase activity.
  • Cryo-electron microscopy to determine structures.
  • Analysis of p97 in complex with its substrate adaptor NPLOC4⋅UFD1L (UN).

Main Results:

  • All seven analyzed MSP mutants demonstrated accelerated substrate unfolding.
  • Mutant p97 complexes showed increased affinity for the UN adaptor and faster substrate processing.
  • Structural data revealed that increased UN affinity stems from a decoupling of p97's nucleotide state and N-terminal domain positioning.

Conclusions:

  • Data support a gain-of-function model for p97-UN-dependent processes in MSP.
  • N-terminal domain movements are critical for adaptor recruitment and substrate processing by p97.
  • Findings highlight the importance of understanding p97 dynamics in MSP pathogenesis.