Increasing prion propensity by hydrophobic insertion.
Prion formation involves the conversion of proteins from a soluble form into an infectious amyloid form. Most yeast prion proteins contain glutamine/asparagine-rich regions that are responsible for prion aggregation. Prion formation by these domains is driven primarily by amino acid composition, not...
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089286&type=printable |
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| author | Aaron C Gonzalez Nelson Kacy R Paul Michelina Petri Noe Flores Ryan A Rogge Sean M Cascarina Eric D Ross |
| author_facet | Aaron C Gonzalez Nelson Kacy R Paul Michelina Petri Noe Flores Ryan A Rogge Sean M Cascarina Eric D Ross |
| author_sort | Aaron C Gonzalez Nelson |
| collection | DOAJ |
| description | Prion formation involves the conversion of proteins from a soluble form into an infectious amyloid form. Most yeast prion proteins contain glutamine/asparagine-rich regions that are responsible for prion aggregation. Prion formation by these domains is driven primarily by amino acid composition, not primary sequence, yet there is a surprising disconnect between the amino acids thought to have the highest aggregation propensity and those that are actually found in yeast prion domains. Specifically, a recent mutagenic screen suggested that both aromatic and non-aromatic hydrophobic residues strongly promote prion formation. However, while aromatic residues are common in yeast prion domains, non-aromatic hydrophobic residues are strongly under-represented. Here, we directly test the effects of hydrophobic and aromatic residues on prion formation. Remarkably, we found that insertion of as few as two hydrophobic residues resulted in a multiple orders-of-magnitude increase in prion formation, and significant acceleration of in vitro amyloid formation. Thus, insertion or deletion of hydrophobic residues provides a simple tool to control the prion activity of a protein. These data, combined with bioinformatics analysis, suggest a limit on the number of strongly prion-promoting residues tolerated in glutamine/asparagine-rich domains. This limit may explain the under-representation of non-aromatic hydrophobic residues in yeast prion domains. Prion activity requires not only that a protein be able to form prion fibers, but also that these fibers be cleaved to generate new independently-segregating aggregates to offset dilution by cell division. Recent studies suggest that aromatic residues, but not non-aromatic hydrophobic residues, support the fiber cleavage step. Therefore, we propose that while both aromatic and non-aromatic hydrophobic residues promote prion formation, aromatic residues are favored in yeast prion domains because they serve a dual function, promoting both prion formation and chaperone-dependent prion propagation. |
| format | Article |
| id | doaj-art-b6a519afec7c42f08aa9f0deaf66ea7e |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-b6a519afec7c42f08aa9f0deaf66ea7e2025-08-20T03:01:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0192e8928610.1371/journal.pone.0089286Increasing prion propensity by hydrophobic insertion.Aaron C Gonzalez NelsonKacy R PaulMichelina PetriNoe FloresRyan A RoggeSean M CascarinaEric D RossPrion formation involves the conversion of proteins from a soluble form into an infectious amyloid form. Most yeast prion proteins contain glutamine/asparagine-rich regions that are responsible for prion aggregation. Prion formation by these domains is driven primarily by amino acid composition, not primary sequence, yet there is a surprising disconnect between the amino acids thought to have the highest aggregation propensity and those that are actually found in yeast prion domains. Specifically, a recent mutagenic screen suggested that both aromatic and non-aromatic hydrophobic residues strongly promote prion formation. However, while aromatic residues are common in yeast prion domains, non-aromatic hydrophobic residues are strongly under-represented. Here, we directly test the effects of hydrophobic and aromatic residues on prion formation. Remarkably, we found that insertion of as few as two hydrophobic residues resulted in a multiple orders-of-magnitude increase in prion formation, and significant acceleration of in vitro amyloid formation. Thus, insertion or deletion of hydrophobic residues provides a simple tool to control the prion activity of a protein. These data, combined with bioinformatics analysis, suggest a limit on the number of strongly prion-promoting residues tolerated in glutamine/asparagine-rich domains. This limit may explain the under-representation of non-aromatic hydrophobic residues in yeast prion domains. Prion activity requires not only that a protein be able to form prion fibers, but also that these fibers be cleaved to generate new independently-segregating aggregates to offset dilution by cell division. Recent studies suggest that aromatic residues, but not non-aromatic hydrophobic residues, support the fiber cleavage step. Therefore, we propose that while both aromatic and non-aromatic hydrophobic residues promote prion formation, aromatic residues are favored in yeast prion domains because they serve a dual function, promoting both prion formation and chaperone-dependent prion propagation.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089286&type=printable |
| spellingShingle | Aaron C Gonzalez Nelson Kacy R Paul Michelina Petri Noe Flores Ryan A Rogge Sean M Cascarina Eric D Ross Increasing prion propensity by hydrophobic insertion. PLoS ONE |
| title | Increasing prion propensity by hydrophobic insertion. |
| title_full | Increasing prion propensity by hydrophobic insertion. |
| title_fullStr | Increasing prion propensity by hydrophobic insertion. |
| title_full_unstemmed | Increasing prion propensity by hydrophobic insertion. |
| title_short | Increasing prion propensity by hydrophobic insertion. |
| title_sort | increasing prion propensity by hydrophobic insertion |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089286&type=printable |
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