title: Opposing effects of glutamine and asparagine govern prion formation by intrinsically disordered proteins.
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.
authors: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors: Randal
authors: R
authors: Halfmann
authors: Simon
authors: S
authors: Alberti
authors: Rajaraman
authors: R
authors: Krishnan
authors: Nicholas
authors: N
authors: Lyle
authors: Charles W
authors: CW
authors: O'Donnell
authors: Oliver D
authors: OD
authors: King
authors: Bonnie
authors: B
authors: Berger
authors: Rohit V
authors: RV
authors: Pappu
authors: Susan
authors: S
authors: Lindquist
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D001216:Asparagine / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D005973:Glutamine / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D008969:Molecular Sequence Data; D010454:Peptide Termination Factors / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D011328:Prions / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D020539:Sequence Analysis, Protein
chemical_list: D000682:Amyloid; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D005973:Glutamine; D001216:Asparagine