Universal protein misfolding intermediates can bypass the proteostasis network and remain soluble and non-functional

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Escherichia Coli

SUBMITTER: Stephen Fried  

LAB HEAD: Stephen D. Fried

PROVIDER: PXD031425 | Pride | 2022-04-13

REPOSITORIES: pride