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The 3.8 Å structure of the U4/U6.U5 tri-snRNP: Insights into spliceosome assembly and catalysis

Structure of a key spliceosomal complex In eukaryotes, when DNA is transcribed into RNA, the primary transcript has protein-coding sequences interrupted by noncoding sequences called introns. Introns are removed by a complex molecular machine, the spliceosome. Wan et al. determined the structure of a key subcomplex, the tri-SNP, that comprises three small nuclear RNAs and more than 30 proteins. The structure, determined by electron microscopy at 3.8 Å resolution, unexpectedly shows a primary RNA transcript bound in the tri-SNP. Further analysis revealed how the spliceosome assembles to achieve its complex functions. Science, this issue p. 466 A key spliceosomal subcomplex reveals how the spliceosome assembles for activity. Splicing of precursor messenger RNA is accomplished by a dynamic megacomplex known as the spliceosome. Assembly of a functional spliceosome requires a preassembled U4/U6.U5 tri-snRNP complex, which comprises the U5 small nuclear ribonucleoprotein (snRNP), the U4 and U6 small nuclear RNA (snRNA) duplex, and a number of protein factors. Here we report the three-dimensional structure of a Saccharomyces cerevisiae U4/U6.U5 tri-snRNP at an overall resolution of 3.8 angstroms by single-particle electron cryomicroscopy. The local resolution for the core regions of the tri-snRNP reaches 3.0 to 3.5 angstroms, allowing construction of a refined atomic model. Our structure contains U5 snRNA, the extensively base-paired U4/U6 snRNA, and 30 proteins including Prp8 and Snu114, which amount to 8495 amino acids and 263 nucleotides with a combined molecular mass of ~1 megadalton. The catalytic nucleotide U80 from U6 snRNA exists in an inactive conformation, stabilized by its base-pairing interactions with U4 snRNA and protected by Prp3. Pre-messenger RNA is bound in the tri-snRNP through base-pairing interactions with U6 snRNA and loop I of U5 snRNA. This structure, together with that of the spliceosome, reveals the molecular choreography of the snRNAs in the activation process of the spliceosomal ribozyme.