1. Molecular basis for the activation of human spliceosome.
- Author
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Zhan X, Lu Y, and Shi Y
- Subjects
- Humans, Ribonucleoprotein, U2 Small Nuclear metabolism, Ribonucleoprotein, U2 Small Nuclear genetics, Models, Molecular, DEAD-box RNA Helicases metabolism, DEAD-box RNA Helicases genetics, Catalytic Domain, Spliceosomes metabolism, RNA Splicing, Cryoelectron Microscopy, RNA Precursors metabolism, RNA Precursors genetics, RNA, Small Nuclear metabolism
- Abstract
The spliceosome executes pre-mRNA splicing through four sequential stages: assembly, activation, catalysis, and disassembly. Activation of the spliceosome, namely remodeling of the pre-catalytic spliceosome (B complex) into the activated spliceosome (B
act complex) and the catalytically activated spliceosome (B* complex), involves major flux of protein components and structural rearrangements. Relying on a splicing inhibitor, we have captured six intermediate states between the B and B* complexes: pre-Bact , Bact -I, Bact -II, Bact -III, Bact -IV, and post-Bact . Their cryo-EM structures, together with an improved structure of the catalytic step I spliceosome (C complex), reveal how the catalytic center matures around the internal stem loop of U6 snRNA, how the branch site approaches 5'-splice site, how the RNA helicase PRP2 rearranges to bind pre-mRNA, and how U2 snRNP undergoes remarkable movement to facilitate activation. We identify a previously unrecognized key role of PRP2 in spliceosome activation. Our study recapitulates a molecular choreography of the human spliceosome during its catalytic activation., (© 2024. The Author(s).)- Published
- 2024
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