Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins
Sequences rich in glutamine (Q) and asparagine (N) residues often fail to fold at the monomer level. This, coupled to their unusual hydrogen-bonding abilities, provides the driving force to switch between disordered monomers and amyloids. Such transitions govern processes as diverse as human protein...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2014
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| Online Access: | http://hdl.handle.net/1721.1/92316 https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0002-2724-7228 |
| _version_ | 1826211370457104384 |
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| author | Halfmann, Randal Arthur Alberti, Simon Krishnan, Rajaraman Lyle, Nicholas O'Donnell, Charles William King, Oliver D. Berger, Bonnie Pappu, Rohit V. Lindquist, Susan |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Halfmann, Randal Arthur Alberti, Simon Krishnan, Rajaraman Lyle, Nicholas O'Donnell, Charles William King, Oliver D. Berger, Bonnie Pappu, Rohit V. Lindquist, Susan |
| author_sort | Halfmann, Randal Arthur |
| collection | MIT |
| description | Sequences rich in glutamine (Q) and asparagine (N) residues often fail to fold at the monomer level. This, coupled to their unusual hydrogen-bonding abilities, provides the driving force to switch between disordered monomers and amyloids. Such transitions govern processes as diverse as human protein-folding diseases, bacterial biofilm assembly, and the inheritance of yeast prions (protein-based genetic elements). A systematic survey of prion-forming domains suggested that Q and N residues have distinct effects on amyloid formation. Here, we use cell biological, biochemical, and computational techniques to compare Q/N-rich protein variants, replacing Ns with Qs and Qs with Ns. We find that the two residues have strong and opposing effects: N richness promotes assembly of benign self-templating amyloids; Q richness promotes formation of toxic nonamyloid conformers. Molecular simulations focusing on intrinsic folding differences between Qs and Ns suggest that their different behaviors are due to the enhanced turn-forming propensity of Ns over Qs. |
| first_indexed | 2024-09-23T15:04:49Z |
| format | Article |
| id | mit-1721.1/92316 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:04:49Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/923162022-10-02T00:26:15Z Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins Halfmann, Randal Arthur Alberti, Simon Krishnan, Rajaraman Lyle, Nicholas O'Donnell, Charles William King, Oliver D. Berger, Bonnie Pappu, Rohit V. Lindquist, Susan Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology. Department of Mathematics Whitehead Institute for Biomedical Research Berger, Bonnie O'Donnell, Charles William Lindquist, Susan Halfmann, Randal Arthur Sequences rich in glutamine (Q) and asparagine (N) residues often fail to fold at the monomer level. This, coupled to their unusual hydrogen-bonding abilities, provides the driving force to switch between disordered monomers and amyloids. Such transitions govern processes as diverse as human protein-folding diseases, bacterial biofilm assembly, and the inheritance of yeast prions (protein-based genetic elements). A systematic survey of prion-forming domains suggested that Q and N residues have distinct effects on amyloid formation. Here, we use cell biological, biochemical, and computational techniques to compare Q/N-rich protein variants, replacing Ns with Qs and Qs with Ns. We find that the two residues have strong and opposing effects: N richness promotes assembly of benign self-templating amyloids; Q richness promotes formation of toxic nonamyloid conformers. Molecular simulations focusing on intrinsic folding differences between Qs and Ns suggest that their different behaviors are due to the enhanced turn-forming propensity of Ns over Qs. National Institutes of Health (U.S.) (Grant GM025874) G. Harold and Leila Y. Mathers Foundation 2014-12-16T14:29:21Z 2014-12-16T14:29:21Z 2011-07 2011-03 Article http://purl.org/eprint/type/JournalArticle 10972765 1097-4164 http://hdl.handle.net/1721.1/92316 Halfmann, Randal, Simon Alberti, Rajaraman Krishnan, Nicholas Lyle, Charles W. O’Donnell, Oliver D. King, Bonnie Berger, Rohit V. Pappu, and Susan Lindquist. “Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins.” Molecular Cell 43, no. 1 (July 2011): 72–84. © 2011 Elsevier Inc. https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0002-2724-7228 en_US http://dx.doi.org/10.1016/j.molcel.2011.05.013 Molecular Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier |
| spellingShingle | Halfmann, Randal Arthur Alberti, Simon Krishnan, Rajaraman Lyle, Nicholas O'Donnell, Charles William King, Oliver D. Berger, Bonnie Pappu, Rohit V. Lindquist, Susan Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins |
| title | Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins |
| title_full | Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins |
| title_fullStr | Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins |
| title_full_unstemmed | Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins |
| title_short | Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins |
| title_sort | opposing effects of glutamine and asparagine govern prion formation by intrinsically disordered proteins |
| url | http://hdl.handle.net/1721.1/92316 https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0002-2724-7228 |
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