Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins

• Main Authors: Halfmann, Randal Arthur (Contributor), Alberti, Simon (Author), Krishnan, Rajaraman (Author), Lyle, Nicholas (Author), O'Donnell, Charles William (Contributor), King, Oliver D. (Author), Berger, Bonnie (Contributor), Pappu, Rohit V (Author), Lindquist, Susan (Contributor)
• Other Authors: Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science (Contributor), Massachusetts Institute of Technology. Department of Mathematics (Contributor), Whitehead Institute for Biomedical Research (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2014-12-16T14:29:21Z.
• Subjects: Article
• Online Access: Get fulltext

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