Molecular basis for the activation of human spliceosome

Xiechao Zhan (), Yichen Lu and Yigong Shi ()
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Xiechao Zhan: Westlake Laboratory of Life Sciences and Biomedicine
Yichen Lu: Westlake Laboratory of Life Sciences and Biomedicine
Yigong Shi: Westlake Laboratory of Life Sciences and Biomedicine

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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 (Bact 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.

Date: 2024
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DOI: 10.1038/s41467-024-50785-0

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