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Sequence features governing aggregation or degradation of prion-like proteins
Enhanced protein aggregation and/or impaired clearance of aggregates can lead to neurodegenerative disorders such as Alzheimer’s Disease, Huntington’s Disease, and prion diseases. Therefore, many protein quality control factors specialize in recognizing and degrading aggregation-prone proteins. Prio...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059496/ https://www.ncbi.nlm.nih.gov/pubmed/30005071 http://dx.doi.org/10.1371/journal.pgen.1007517 |
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author | Cascarina, Sean M. Paul, Kacy R. Machihara, Satoshi Ross, Eric D. |
author_facet | Cascarina, Sean M. Paul, Kacy R. Machihara, Satoshi Ross, Eric D. |
author_sort | Cascarina, Sean M. |
collection | PubMed |
description | Enhanced protein aggregation and/or impaired clearance of aggregates can lead to neurodegenerative disorders such as Alzheimer’s Disease, Huntington’s Disease, and prion diseases. Therefore, many protein quality control factors specialize in recognizing and degrading aggregation-prone proteins. Prions, which generally result from self-propagating protein aggregates, must therefore evade or outcompete these quality control systems in order to form and propagate in a cellular context. We developed a genetic screen in yeast that allowed us to explore the sequence features that promote degradation versus aggregation of a model glutamine/asparagine (Q/N)-rich prion domain from the yeast prion protein, Sup35, and two model glycine (G)-rich prion-like domains from the human proteins hnRNPA1 and hnRNPA2. Unexpectedly, we found that aggregation propensity and degradation propensity could be uncoupled in multiple ways. First, only a subset of classically aggregation-promoting amino acids elicited a strong degradation response in the G-rich prion-like domains. Specifically, large aliphatic residues enhanced degradation of the prion-like domains, whereas aromatic residues promoted prion aggregation without enhancing degradation. Second, the degradation-promoting effect of aliphatic residues was suppressed in the context of the Q/N-rich prion domain, and instead led to a dose-dependent increase in the frequency of spontaneous prion formation. Degradation suppression correlated with Q/N content of the surrounding prion domain, potentially indicating an underappreciated activity for these residues in yeast prion domains. Collectively, these results provide key insights into how certain aggregation-prone proteins may evade protein quality control degradation systems. |
format | Online Article Text |
id | pubmed-6059496 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-60594962018-08-09 Sequence features governing aggregation or degradation of prion-like proteins Cascarina, Sean M. Paul, Kacy R. Machihara, Satoshi Ross, Eric D. PLoS Genet Research Article Enhanced protein aggregation and/or impaired clearance of aggregates can lead to neurodegenerative disorders such as Alzheimer’s Disease, Huntington’s Disease, and prion diseases. Therefore, many protein quality control factors specialize in recognizing and degrading aggregation-prone proteins. Prions, which generally result from self-propagating protein aggregates, must therefore evade or outcompete these quality control systems in order to form and propagate in a cellular context. We developed a genetic screen in yeast that allowed us to explore the sequence features that promote degradation versus aggregation of a model glutamine/asparagine (Q/N)-rich prion domain from the yeast prion protein, Sup35, and two model glycine (G)-rich prion-like domains from the human proteins hnRNPA1 and hnRNPA2. Unexpectedly, we found that aggregation propensity and degradation propensity could be uncoupled in multiple ways. First, only a subset of classically aggregation-promoting amino acids elicited a strong degradation response in the G-rich prion-like domains. Specifically, large aliphatic residues enhanced degradation of the prion-like domains, whereas aromatic residues promoted prion aggregation without enhancing degradation. Second, the degradation-promoting effect of aliphatic residues was suppressed in the context of the Q/N-rich prion domain, and instead led to a dose-dependent increase in the frequency of spontaneous prion formation. Degradation suppression correlated with Q/N content of the surrounding prion domain, potentially indicating an underappreciated activity for these residues in yeast prion domains. Collectively, these results provide key insights into how certain aggregation-prone proteins may evade protein quality control degradation systems. Public Library of Science 2018-07-13 /pmc/articles/PMC6059496/ /pubmed/30005071 http://dx.doi.org/10.1371/journal.pgen.1007517 Text en © 2018 Cascarina et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Cascarina, Sean M. Paul, Kacy R. Machihara, Satoshi Ross, Eric D. Sequence features governing aggregation or degradation of prion-like proteins |
title | Sequence features governing aggregation or degradation of prion-like proteins |
title_full | Sequence features governing aggregation or degradation of prion-like proteins |
title_fullStr | Sequence features governing aggregation or degradation of prion-like proteins |
title_full_unstemmed | Sequence features governing aggregation or degradation of prion-like proteins |
title_short | Sequence features governing aggregation or degradation of prion-like proteins |
title_sort | sequence features governing aggregation or degradation of prion-like proteins |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059496/ https://www.ncbi.nlm.nih.gov/pubmed/30005071 http://dx.doi.org/10.1371/journal.pgen.1007517 |
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