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ORIGINAL ARTICLES

Structural insights into human exon-defined spliceosome prior to activation

Wenyu Zhang1 , Xiaofeng Zhang2,3,4 , Xiechao Zhan2,3,4 , Rui Bai2,3,4 , Jianlin Lei1 , Chuangye Yan1,* , Yigong Shi1,2,3,4,*

1Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
2Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
3Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
4Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
* Correspondence: Chuangye Yan(yancy2019@tsinghua.edu.cn)Yigong Shi(syg@westlake.edu.cn)

Spliceosome is often assembled across an exon and undergoes rearrangement to span a neighboring intron. Most states of the intron-defined spliceosome have been structurally characterized. However, the structure of a fully assembled exon-defined spliceosome remains at large. During spliceosome assembly, the pre-catalytic state (B complex) is converted from its precursor (pre-B complex). Here we report atomic structures of the exon-defined human spliceosome in four sequential states: mature pre-B, late pre-B, early B, and mature B. In the previously unknown late pre-B state, U1 snRNP is already released but the remaining proteins are still in the pre-B state; unexpectedly, the RNAs are in the B state, with U6 snRNA forming a duplex with 5′-splice site and U5 snRNA recognizing the 3′-end of the exon. In the early and mature B complexes, the B-specific factors are stepwise recruited and specifically recognize the exon 3′-region. Our study reveals key insights into the assembly of the exon-defined spliceosomes and identifies mechanistic steps of the pre-B-to-B transition.

https://doi.org/10.1038/s41422-024-00949-w

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