Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains

Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasi...

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Veröffentlicht in:International journal of molecular sciences 2021-08, Vol.22 (16), p.8944
Hauptverfasser: Cascarina, Sean M., Kaplan, Joshua P., Elder, Mikaela R., Brookbank, Lindsey, Ross, Eric D.
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container_issue 16
container_start_page 8944
container_title International journal of molecular sciences
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creator Cascarina, Sean M.
Kaplan, Joshua P.
Elder, Mikaela R.
Brookbank, Lindsey
Ross, Eric D.
description Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation.
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source Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central
subjects Amino acids
Asparagine
Biodegradation
Domains
Glutamine
Glycine
Hydrophobicity
Libraries
Mutagenesis
Proteasomes
Protein interaction
Proteins
Proteomes
Sensitivity
Ubiquitin
Yeast
title Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains
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