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Structural insights into human exon-defined spliceosome prior to activation

Wenyu Zhang¹ , Xiaofeng Zhang^2,3,4 , Xiechao Zhan^2,3,4 , Rui Bai^2,3,4 , Jianlin Lei¹ , Chuangye Yan^1,* , Yigong Shi^1,2,3,4,*

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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