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Introns are removed from eukaryotic premessenger RNA by the spliceosome. The spliceosome is assembled and disassembled during the course of each splicing reaction, and the RNA-protein remodeling involved is carried out by RNA helicases, whose activities must be closely regulated. Mozaffari-Jovin et al. (p. 80, published online 23 May) determined the crystal structure of the human Brr helicase in complex with the Jab1 domain of the Prp1 spliceosomal protein. The C-terminal tail of the Prp8 Jab1 domain inserts into the RNA-binding tunnel of Brr2, disrupting interaction of the RNA with the conserved helicase motifs inside tunnel. The temporal regulation of Brr2 RNA-binding and adenosine triphosphatase activity likely avoids premature disassembly of structures required during the splicing reaction.
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.