title: Inhibition of RNA helicase Brr2 by the C-terminal tail of the spliceosomal protein Prp8.
abstract: The Ski2-like RNA helicase Brr2 is a core component of the spliceosome that must be tightly regulated to ensure correct timing of spliceosome activation. Little is known about mechanisms of regulation of Ski2-like helicases by protein cofactors. Here we show by crystal structure and biochemical analyses that the Prp8 protein, a major regulator of the spliceosome, can insert its C-terminal tail into Brr2's RNA-binding tunnel, thereby intermittently blocking Brr2's RNA-binding, adenosine triphosphatase, and U4/U6 unwinding activities. Inefficient Brr2 repression is the only recognizable phenotype associated with certain retinitis pigmentosa-linked Prp8 mutations that map to its C-terminal tail. Our data show how a Ski2-like RNA helicase can be reversibly inhibited by a protein cofactor that directly competes with RNA substrate binding.
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Mozaffari-Jovin
authors.forename: Traudy
authors.initials: T
authors.lastname: Wandersleben
authors.forename: Karine F
authors.initials: KF
authors.lastname: Santos
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Will
authors.forename: Reinhard
authors.initials: R
authors.lastname: Lührmann
authors.forename: Markus C
authors.initials: MC
authors.lastname: Wahl
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism*; D020365:RNA Helicases / Q000378:metabolism; D016601:RNA-Binding Proteins; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000378:metabolism; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000378:metabolism; D017411:Ribonucleoproteins, Small Nuclear / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D017381:Spliceosomes / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D002352:Carrier Proteins; C077018:PRP8 protein, S cerevisiae; C115374:PRPF8 protein, human; D016601:RNA-Binding Proteins; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; D017415:Ribonucleoprotein, U5 Small Nuclear; D017411:Ribonucleoproteins, Small Nuclear; C545711:SNRNP200 protein, human; D029701:Saccharomyces cerevisiae Proteins; D012313:RNA; C104158:BRR2 protein, S cerevisiae; D020365:RNA Helicases