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The mechanism of the second step of pre‐mRNA splicing

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Abstract The molecular mechanisms of the second step of pre‐mRNA splicing in yeast and higher eukaryotes are reviewed. The important elements in the pre‐mRNA, the participating proteins, and the proposed secondary structures and roles of the snRNAs are described. The sequence of events in the second step is presented, focusing on the actions of the proteins in setting up and facilitating the second reaction. Mechanisms for avoiding errors in splicing are discussed. WIREs RNA 2012, 3:331–350. doi: 10.1002/wrna.112 This article is categorized under: RNA Processing > Splicing Mechanisms

Proposed conformations of the snRNAs in the active spliceosome. Yeast sequences are shown; the key bases and interactions are conserved between species. (a) The snRNAs and pre‐mRNA at the time of the first reaction, showing many of the key bases. (b) and (c) Alternative conformations of the U6 ISL portion of the structure in (a). (d) Alternative conformation of U2 stem IIa. (e) The snRNAs and the pre‐mRNA at the time of the second reaction, emphasizing the overall arrangement of the snRNAs and the altered pairing of U5. In the pre‐mRNA and splicing intermediates, exons are shown in orange, and the intron, in pink. U2 is purple, U6 is cyan, and U5 is green. Stems, loops, and helices are labeled, and numbering of snRNA bases is shown in (a). Base pairs are indicated by solid black lines either between bases or between line drawings of the RNAs. Dotted lines indicate A–C pairings. The reactions in splicing are shown by blue arrows in (a) and (e). Bases critical for the second step are circled in red in panel (a). Non‐conserved exon bases are shown as E's; in (e) the E's are numbered relative to the splice junctions. Genetically inferred non‐base‐pairing interactions are indicated by green lines connecting bases in panels (a) and (e). Photochemical crosslinks are shown in burgundy in (e). U2 stems IIa and IIc are crosshatched in (a) and (d).

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Key features of the pre‐mRNA for the second step. Intron bases and the distance between the branchpoint and the 3′ splice site are indicated. The exon bases at the splice junctions and exonic splicing enhancer (ESE) are also shown.

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The two transesterification reactions of pre‐mRNA splicing. The groups involved in the first reaction are highlighted in magenta, and those in the second, in blue. Phosphates are shown as circled P's.

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Protein dynamics before, during and after the second step. The pathway shown begins late in the first step and extends through disassembly of the spliceosome. Exon 1 is shown in purple, the intron in blue, and exon 2 in red. Each protein is labeled. The yellow spliceosome includes three snRNAs and tens of proteins. Many of the proteins shown in contact in the figure are indeed in contact in the spliceosome, but not all (see the text for clarification). In the top panel, Prp16 activates the spliceosome, indicated by its blue and red surface. In the middle panel, Prp22 is shown moving along the mRNA powered by ATP hydrolysis. Species labeled as ‘transient’ have not been detected for wild‐type substrates.

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