National Natural Science Foundation of China (NSFC)
31930059
China
Citation
Journal: Cell Res / Year: 2024 Title: Structural insights into human exon-defined spliceosome prior to activation. Authors: Wenyu Zhang / Xiaofeng Zhang / Xiechao Zhan / Rui Bai / Jianlin Lei / Chuangye Yan / Yigong Shi / Abstract: 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, ...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.
A: pre-mRNA 6A: U6 snRNA 6a: U6 snRNA-associated Sm-like protein LSm2 6b: U6 snRNA-associated Sm-like protein LSm3 6c: U6 snRNA-associated Sm-like protein LSm4 6d: U6 snRNA-associated Sm-like protein LSm5 6e: U6 snRNA-associated Sm-like protein LSm6 6f: U6 snRNA-associated Sm-like protein LSm7 6g: U6 snRNA-associated Sm-like protein LSm8 5A: U5 snRNA 5B: Pre-mRNA-processing-splicing factor 8 5C: 116 kDa U5 small nuclear ribonucleoprotein component 5D: U5 small nuclear ribonucleoprotein 200 kDa helicase 5E: U5 small nuclear ribonucleoprotein 40 kDa protein 5a: Isoform SM-B of Small nuclear ribonucleoprotein-associated proteins B and B' 5b: Small nuclear ribonucleoprotein Sm D1 5c: Small nuclear ribonucleoprotein Sm D2 5d: Small nuclear ribonucleoprotein F 5e: Small nuclear ribonucleoprotein E 5f: Small nuclear ribonucleoprotein G 5g: Small nuclear ribonucleoprotein Sm D3 4A: U4 snRNA 4B: U4/U6 small nuclear ribonucleoprotein Prp3 4C: U4/U6 small nuclear ribonucleoprotein Prp4 4D: U4/U6 small nuclear ribonucleoprotein Prp31 4E: NHP2-like protein 1 4F: Thioredoxin-like protein 4A 4G: Pre-mRNA-processing factor 6 4R: RNA-binding protein 42 4S: U4/U6.U5 tri-snRNP-associated protein 1 4T: U4/U6.U5 tri-snRNP-associated protein 2 4U: Probable ATP-dependent RNA helicase DDX23 4X: U4/U6.U5 small nuclear ribonucleoprotein 27 kDa protein 4Y: Serine/threonine-protein kinase PRP4 homolog 4a: Isoform SM-B of Small nuclear ribonucleoprotein-associated proteins B and B' 4b: Small nuclear ribonucleoprotein Sm D1 4c: Small nuclear ribonucleoprotein Sm D2 4d: Small nuclear ribonucleoprotein F 4e: Small nuclear ribonucleoprotein E 4f: Small nuclear ribonucleoprotein G 4g: Small nuclear ribonucleoprotein Sm D3 2A: U2 snRNA 2B: U2 small nuclear ribonucleoprotein A' 2C: U2 small nuclear ribonucleoprotein B'' 2D: Splicing factor 3A subunit 1 2E: Splicing factor 3A subunit 2 2F: Splicing factor 3A subunit 3 2G: Splicing factor 3B subunit 1 2H: Splicing factor 3B subunit 2 2I: Splicing factor 3B subunit 3 2J: Splicing factor 3B subunit 4 2K: Splicing factor 3B subunit 6 2L: PHD finger-like domain-containing protein 5A 2M: Splicing factor 3B subunit 5 2a: Isoform SM-B of Small nuclear ribonucleoprotein-associated proteins B and B' 2b: Small nuclear ribonucleoprotein Sm D1 2c: Small nuclear ribonucleoprotein Sm D2 2d: Small nuclear ribonucleoprotein F 2e: Small nuclear ribonucleoprotein E 2f: Small nuclear ribonucleoprotein G 2g: Small nuclear ribonucleoprotein Sm D3 hetero molecules
Mass: 117264.977 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: Q13523, non-specific serine/threonine protein kinase
#46: Protein
PHDfinger-likedomain-containingprotein5A / PHD finger-like domain protein 5A / Splicing factor 3B-associated 14 kDa protein / SF3b14b
Mass: 12427.524 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q7RTV0
Mass: 58536.105 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: O43172
#25: Protein
U4/U6smallnuclearribonucleoproteinPrp31 / Pre-mRNA-processing factor 31 / Serologically defined breast cancer antigen NY-BR-99 / U4/U6 snRNP ...Pre-mRNA-processing factor 31 / Serologically defined breast cancer antigen NY-BR-99 / U4/U6 snRNP 61 kDa protein / Protein 61K / hPrp31
Mass: 55528.969 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q8WWY3
+
U4/U6.U5 tri-snRNP-associated protein ... , 2 types, 2 molecules 4S4T
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