title: Novel regulatory principles of the spliceosomal Brr2 RNA helicase and links to retinal disease in humans.
abstract: For each round of pre-mRNA splicing, a spliceosome is assembled anew on its substrate. RNA-protein remodeling events required for spliceosome assembly, splicing catalysis, and spliceosome disassembly are driven and controlled by a conserved group of ATPases/RNA helicases. The activities of most of these enzymes are timed by their recruitment to the spliceosome. The Brr2 enzyme, however, which mediates spliceosome catalytic activation, is a stable subunit of the spliceosome, and thus, requires special regulation. Recent structural and functional studies have revealed diverse mechanisms whereby an RNaseH-like and a Jab1/MPN-like domain of the Prp8 protein regulate Brr2 activity during splicing both positively and negatively. Reversible Brr2 inhibition might in part be achieved via an intrinsically unstructured element of the Prp8 Jab1/MPN domain, a concept widespread in biological systems. Mutations leading to changes in the Prp8 Jab1/MPN domain, which are linked to a severe form of retinitis pigmentosa, disrupt Jab1/MPN-mediated regulation of Brr2.
authors.affiliation: Dept. of Cellular Biochemistry; Max Planck Institute for Biophysical Chemistry; Am Fassberg 11; Göttingen, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Mozaffari-Jovin
authors.affiliation: Laboratory of Structural Biochemistry; Freie Universität Berlin; Takustr. 6; Berlin, Germany.
authors.forename: Traudy
authors.initials: T
authors.lastname: Wandersleben
authors.affiliation: Laboratory of Structural Biochemistry; Freie Universität Berlin; Takustr. 6; Berlin, Germany.
authors.forename: Karine F
authors.initials: KF
authors.lastname: Santos
authors.affiliation: Dept. of Cellular Biochemistry; Max Planck Institute for Biophysical Chemistry; Am Fassberg 11; Göttingen, Germany.
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Will
authors.affiliation: Dept. of Cellular Biochemistry; Max Planck Institute for Biophysical Chemistry; Am Fassberg 11; Göttingen, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Lührmann
authors.affiliation: Laboratory of Structural Biochemistry; Freie Universität Berlin; Takustr. 6; Berlin, Germany.
authors.forename: Markus C
authors.initials: MC
authors.lastname: Wahl
mesh_terms: D000075686:COP9 Signalosome Complex; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D012164:Retinal Diseases / Q000235:genetics* / Q000378:metabolism*; D017411:Ribonucleoproteins, Small Nuclear / Q000737:chemistry / Q000378:metabolism*; D017381:Spliceosomes / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C115374:PRPF8 protein, human; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear; C545711:SNRNP200 protein, human; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex
keywords: Pre-mRNA splicing; RNA helicase; RNA-protein complex; retinitis pigmentosa; spliceosome catalytic activation