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

Daniel Allen Nissley, Yang Jiang, Fabio Trovato, Ian Sitarik, Karthik Narayan, Edward P O'Brien
2021 bioRxiv   pre-print
Misfolded protein conformations with decreased functionality can bypass the proteostasis machinery and remain soluble in vivo. This is an unexpected phenomenon as several cellular quality control mechanisms have evolved to rid cells of misfolded proteins. Three questions, then, are: how is it structurally possible for long-lived, soluble, misfolded proteins to bypass the proteostasis machinery and processes? How widespread are these soluble, misfolded states across the proteome? And how long do
more » ... they persist for? Here, 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 find 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 can 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, in which a protein segment threads through a loop formed by another portion of the protein that is not found in the native state. The surface properties of these misfolded states are native like, allowing them to bypass the proteostasis machinery and processes to remain soluble, while their entanglements make these states long-lived kinetic traps, as disentanglement requires unfolding of already folded portions of the protein. In terms of function, one-third of proteins have subpopulations that misfold into less-functional states that have structurally perturbed functional sites yet remain soluble. These results explain how proteins misfold into soluble, non-functional conformations that bypass cellular quality controls, and indicate that, unexpectedly, this is a wide-spread cellular phenomenon that can lead to reduced protein function across the cytosolic proteome. Such entanglements are observed in many native structures, suggesting the non-native entanglements we observe are plausible. More broadly, these near-native entangled structures suggest a hypothesis for how synonymous mutations can modulate downstream protein structure and function, with these mutations partitioning nascent proteins between these kinetically trapped states.
doi:10.1101/2021.08.18.456613 fatcat:nqoh7wxxgfgrxeblu7fk2mc77q