Abstract
Pre-mRNA splicing requires the assembly, remodeling, and disassembly of the multi-megadalton ribonucleoprotein complex called the spliceosome1. Recent studies have shed light on spliceosome assembly and remodeling for catalysis2–6, but the mechanism of disassembly remains unclear. Here, we report 2.6 to 3.2 Å resolution cryo-electron microscopy structures of nematode and human terminal intron-lariat spliceosomes along with biochemical and genetic data. Our results uncover how four disassembly factors and the conserved RNA helicase DHX15 initiate spliceosome disassembly. The disassembly factors probe large inner and outer spliceosome surfaces to detect the release of ligated mRNA. Two of these factors, TFIP11 and C19L1, and three general spliceosome subunits, SYF1, SYF2 and SDE2, then dock and activate DHX15 on the catalytic U6 snRNA to initiate disassembly. U6 thus controls both the start5 and end of pre-mRNA splicing. Taken together, our results explain the molecular basis of canonical spliceosome disassembly and provide a framework to understand general spliceosomal RNA helicase control and the discard of aberrant spliceosomes.
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Supplementary information
Supplementary Information
This file contains Supplementary Text 1; Supplementary Figures 1-6; Supplementary Tables 3-5 and legends for Supplementary Videos 1-5.
Supplementary Table 1
Guide to coordinate models and cryo-EM maps.
Supplementary Table 2
Overview of Ce spliceosome subunit orthologs and their mutant phenotypes.
Supplementary Video 1
Structure of the Ce ILS.
Supplementary Video 2
Structure of the Ce ILS.
Supplementary Video 3
Integrative model of the human ILS.
Supplementary Video 4
Revised model of the human P complex.
Supplementary Video 5
Model of terminal spliceosome disassembly.
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Vorländer, M.K., Rothe, P., Kleifeld, J. et al. Mechanism for the initiation of spliceosome disassembly. Nature (2024). https://doi.org/10.1038/s41586-024-07741-1
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DOI: https://doi.org/10.1038/s41586-024-07741-1
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