PXD031425

PXD031425 is an original dataset announced via ProteomeXchange.

Title	Universal protein misfolding intermediates can bypass the proteostasis network and remain soluble and non-functional
Description	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 all proteins exhibit subpopulations of misfolded conformations that are likely to bypass molecular chaperones, avoid aggregation, and not be degraded. These misfolded states may persist for months or longer for some proteins. Structurally characterizing these misfolded states, we observe they have a large amount of native structure, but also contain localized misfolded regions from non-native changes in entanglement. These misfolded states are native-like, suggesting they may bypass the proteostasis machinery to remain soluble. In terms of function, we predict that one-third of proteins have subpopulations that misfold into less-functional states that remain soluble. To experimentally test for the presence of entanglements and the kinetic persistence of these states we ran protease digestion mass spectrometry on glycerol-3-phosphate dehydrogenase. We find that the common changes in its digestion pattern at 1 min, 5 min, and 120 min are explained by our predicted near-native entangled states. These results suggest an explanation for how proteins misfold into soluble, non-functional conformations that bypass cellular quality controls across the E. coli proteome.
HostingRepository	PRIDE
AnnounceDate	2022-04-13
AnnouncementXML	Submission_2022-04-13_03:45:14.536.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Stephen Fried
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-03 13:01:28	ID requested
⏵ 1	2022-04-13 03:45:14	announced

Dataset with its publication pending

submitter keyword: Protein Misfolding, Proteostasis

Stephen D. Fried
contact affiliation	Johns Hopkins University, Chemistry Department, Fried Lab, USA (lab head)
contact email	sdfried@jhu.edu
lab head
Stephen Fried
contact affiliation	Johns Hopkins University
contact email	sdfried@jhu.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031425
     1. Label: PRIDE project
     2. Name: Universal protein misfolding intermediates can bypass the proteostasis network and remain soluble and non-functional