title: Controlling the prion propensity of glutamine/asparagine-rich proteins.
abstract: The yeast Saccharomyces cerevisiae can harbor a number of distinct prions. Most of the yeast prion proteins contain a glutamine/asparagine (Q/N) rich region that drives prion formation. Prion-like domains, defined as regions with high compositional similarity to yeast prion domains, are common in eukaryotic proteomes, and mutations in various human proteins containing prion-like domains have been linked to degenerative diseases, including amyotrophic lateral sclerosis. Here, we discuss a recent study in which we utilized two strategies to generate prion activity in non-prion Q/N-rich domains. First, we made targeted mutations in four non-prion Q/N-rich domains, replacing predicted prion-inhibiting amino acids with prion-promoting amino acids. All four mutants formed foci when expressed in yeast, and two acquired bona fide prion activity. Prion activity could be generated with as few as two mutations, suggesting that many non-prion Q/N-rich proteins may be just a small number of mutations from acquiring aggregation or prion activity. Second, we created tandem repeats of short prion-prone segments, and observed length-dependent prion activity. These studies demonstrate the considerable progress that has been made in understanding the sequence basis for aggregation of prion and prion-like domains, and suggest possible mechanisms by which new prion domains could evolve.
authors.affiliation: a Department of Biochemistry and Molecular Biology ; Colorado State University ; Fort Collins , CO USA.
authors.forename: Kacy R
authors.initials: KR
authors.lastname: Paul
authors.affiliation: a Department of Biochemistry and Molecular Biology ; Colorado State University ; Fort Collins , CO USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Ross
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D001216:Asparagine / Q000737:chemistry*; D005973:Glutamine / Q000737:chemistry*; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism
chemical_list: D000682:Amyloid; D011328:Prions; D005973:Glutamine; D001216:Asparagine
keywords: Sup35; amyloid; prion; protein aggregation; yeast