Evidence map›Paper›PMID 35654797›Full record

ArticleNature communications2022

Universal protein misfolding intermediates can bypass the proteostasis network and remain soluble and less functional.

Daniel A Nissley, Yang Jiang, Fabio Trovato, Ian Sitarik, Karthik B Narayan, Philip To, Yingzi Xia, Stephen D Fried, Edward P O'Brien

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
36citing papers in PubMed, 1 pooled it
–field-weighted citation impact
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

36 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Article
  3. Review
  4. Subcellular localization as a driver of protein function.Nature reviews. Molecular cell biology · 2026
    Review
  5. Review
  6. Article
  7. Article
  8. Article
  9. Review
  10. Article
  11. Review
  12. Article
  13. Review
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. 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

9 authors.

Daniel A Nissley *Department of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA.
Yang Jiang *Department of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA.ORCID 0000-0003-1100-9177
Fabio TrovatoDepartment of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA.ORCID 0000-0002-1324-0930
Ian SitarikDepartment of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA.
Karthik B NarayanDepartment of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA.ORCID 0000-0003-1047-0375
Philip ToDepartment of Chemistry, Johns Hopkins University, Baltimore, MD, 21218, USA.
Yingzi XiaDepartment of Chemistry, Johns Hopkins University, Baltimore, MD, 21218, USA.
Stephen D FriedDepartment of Chemistry, Johns Hopkins University, Baltimore, MD, 21218, USA.ORCID 0000-0003-2494-2193
Edward P O'BrienDepartment of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA. epo2@psu.edu.ORCID 0000-0001-9809-3273

Funding

Translation Kinetics and their Effects on Protein Structure and Function, mRNA half-lives, and Cellular PhenotypeR35GM124818 · NIGMS · PENNSYLVANIA STATE UNIVERSITY, THE · PI Edward Patrick O'Brien · 2017 to 2026
$4.0M
Watching Proteins Fold (or Misfold) in vivo with Mass SpectrometryDP2GM140926 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI FRIED, STEPHEN DAVID · 2020 to 2020
$2.3M
NIGMS NIH HHS DP2 GM140926NIGMS NIH HHS R35 GM124818
6 · The paper itself

Abstract

Some misfolded protein conformations can bypass proteostasis machinery and remain soluble in vivo. This is an unexpected observation, as cellular quality control mechanisms should remove misfolded proteins. Three questions, then, are: how do long-lived, soluble, misfolded proteins bypass proteostasis? How widespread are such misfolded states? And how long do they persist? We address these questions using coarse-grain molecular dynamics simulations of the synthesis, termination, and post-translational dynamics of a representative set of cytosolic E. coli proteins. We predict that half of proteins exhibit misfolded subpopulations that bypass molecular chaperones, avoid aggregation, and will not be rapidly degraded, with some misfolded states persisting for months or longer. The surface properties of these misfolded states are native-like, suggesting they will remain soluble, while self-entanglements make them long-lived kinetic traps. In terms of function, we predict that one-third of proteins can misfold into soluble less-functional states. For the heavily entangled protein glycerol-3-phosphate dehydrogenase, limited-proteolysis mass spectrometry experiments interrogating misfolded conformations of the protein are consistent with the structural changes predicted by our simulations. These results therefore provide an explanation for how proteins can misfold into soluble conformations with reduced functionality that can bypass proteostasis, and indicate, unexpectedly, this may be a wide-spread phenomenon.

Indexed as

Escherichia coli ProteinsProteostasisEscherichia coliMolecular ChaperonesProtein FoldingProteolysisEscherichia coli ProteinsMolecular Chaperones

Identifiers

PMID35654797
PMCPMC9163053

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.