Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins
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Halfmann-2011-Opposing Effects of.pdf
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Author(s)
Halfmann, Randal Arthur
Alberti, Simon
Krishnan, Rajaraman
Lyle, Nicholas
O'Donnell, Charles William
King, Oliver D.
Berger, Bonnie
Pappu, Rohit V.
Lindquist, Susan
Date Issued
July 2011
Journal
Molecular Cell
Publisher
Elsevier
Citation
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.
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Final published version
Abstract
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.
MIT Department
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
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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.
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DOI of Published Version
https://doi.org/10.1016/j.molcel.2011.05.013
