Evidence map›Paper›PMID 31623962›Full record

ArticleStructure (London, England : 1993)2019

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

Emily E Blythe, Stephanie N Gates, Raymond J Deshaies, Andreas Martin

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Structure (London, England : 1993), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.

0numbers the graph read from it
0cells of the map it votes in
56citing papers in PubMed
7.7field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

56 citing papers in PubMed, 76 citations in OpenAlex.

  1. Review
  2. Article
  3. Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Article
  9. Article
  10. Article
  11. Article
  12. Article
  13. Article
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Allosteric activation of VCP, an AAA unfoldase, by small molecule mimicry.Proceedings of the National Academy of Sciences of the United States of America · 2024
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors at 2 institutions in 1 country.

Emily E BlytheDivision 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.
Stephanie N GatesDepartment of Molecular & Cell Biology, University of California, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA.
Raymond J DeshaiesDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Amgen Research, Thousand Oaks, CA 91320, USA.
Andreas MartinDepartment of Molecular & Cell Biology, University of California, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: a.martin@berkeley.edu.
California Institute of Technology · USHoward Hughes Medical Institute · US

Funding

ATP-Dependent Protein Unfolding and Translocation by the Eukaryotic ProteasomeR01GM094497 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI MARTIN, ANDREAS · 2011 to 2024
$3.7M
Howard Hughes Medical InstituteNIGMS NIH HHS R01 GM094497
6 · The paper itself

Abstract

Valosin-containing protein (VCP)/p97 is an essential ATP-dependent protein unfoldase. Dominant mutations in p97 cause multisystem proteinopathy (MSP), a disease affecting the brain, muscle, and bone. Despite the identification of numerous pathways that are perturbed in MSP, the molecular-level defects of these p97 mutants are not completely understood. Here, we use biochemistry and cryoelectron microscopy to explore the effects of MSP mutations on the unfoldase activity of p97 in complex with its substrate adaptor NPLOC4⋅UFD1L (UN). We show that all seven analyzed MSP mutants unfold substrates faster. Mutant homo- and heterohexamers exhibit tighter UN binding and faster substrate processing. Our structural studies suggest that the increased UN affinity originates from a decoupling of p97's nucleotide state and the positioning of its N-terminal domains. Together, our data support a gain-of-function model for p97-UN-dependent processes in MSP and underscore the importance of N-terminal domain movements for adaptor recruitment and substrate processing by p97.

Indexed as

MutationBinding SitesCloning, MolecularCryoelectron MicroscopyEscherichia coliFluorescence Resonance Energy TransferGene ExpressionGenetic VectorsHumansIntracellular Signaling Peptides and ProteinsKineticsModels, MolecularNuclear ProteinsProtein BindingProtein ConformationProtein FoldingIntracellular Signaling Peptides and ProteinsNPLOC4 protein, humanNuclear ProteinsRecombinant ProteinsUFD1 protein, humanValosin Containing ProteinAAA+ ATPaseATP-dependent protein unfoldingmultisystem proteinopathyp97Ufd1-Npl4VCP

Identifiers

PMID31623962
PMCPMC6929323
OpenAlexW2979586066

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.