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| Title | Structural insights into the cross-exon to cross-intron spliceosome switch. |
|---|---|
| Journal, issue, pages | Nature, Year 2024 |
| Publish date | May 22, 2024 |
 Authors | Zhenwei Zhang / Vinay Kumar / Olexandr Dybkov / Cindy L Will / Jiayun Zhong / Sebastian E J Ludwig / Henning Urlaub / Berthold Kastner / Holger Stark / Reinhard Lührmann /   |
| PubMed Abstract | Early spliceosome assembly can occur through an intron-defined pathway, whereby U1 and U2 small nuclear ribonucleoprotein particles (snRNPs) assemble across the intron. Alternatively, it can occur ...Early spliceosome assembly can occur through an intron-defined pathway, whereby U1 and U2 small nuclear ribonucleoprotein particles (snRNPs) assemble across the intron. Alternatively, it can occur through an exon-defined pathway, whereby U2 binds the branch site located upstream of the defined exon and U1 snRNP interacts with the 5' splice site located directly downstream of it. The U4/U6.U5 tri-snRNP subsequently binds to produce a cross-intron (CI) or cross-exon (CE) pre-B complex, which is then converted to the spliceosomal B complex. Exon definition promotes the splicing of upstream introns and plays a key part in alternative splicing regulation. However, the three-dimensional structure of exon-defined spliceosomal complexes and the molecular mechanism of the conversion from a CE-organized to a CI-organized spliceosome, a pre-requisite for splicing catalysis, remain poorly understood. Here cryo-electron microscopy analyses of human CE pre-B complex and B-like complexes reveal extensive structural similarities with their CI counterparts. The results indicate that the CE and CI spliceosome assembly pathways converge already at the pre-B stage. Add-back experiments using purified CE pre-B complexes, coupled with cryo-electron microscopy, elucidate the order of the extensive remodelling events that accompany the formation of B complexes and B-like complexes. The molecular triggers and roles of B-specific proteins in these rearrangements are also identified. We show that CE pre-B complexes can productively bind in trans to a U1 snRNP-bound 5' splice site. Together, our studies provide new mechanistic insights into the CE to CI switch during spliceosome assembly and its effect on pre-mRNA splice site pairing at this stage. |
 External links | Nature / PubMed:38778104 |
| Methods | EM (single particle) |
| Resolution | 3.1 - 9.6 Å |
| Structure data | EMDB-18542, PDB-8qoz: EMDB-18544, PDB-8qp8: EMDB-18545, PDB-8qp9: EMDB-18546, PDB-8qpa: EMDB-18547, PDB-8qpb: EMDB-18548, PDB-8qpe: EMDB-18555, PDB-8qpk: EMDB-18718, PDB-8qxd: EMDB-18781, PDB-8qzs: EMDB-18786, PDB-8r08: EMDB-18787, PDB-8r09: EMDB-18788, PDB-8r0a: EMDB-18789, PDB-8r0b: EMDB-19349, PDB-8rm5: |
| Chemicals |  ChemComp-IHP: |
| Source |
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 Keywords |  SPLICING / spliceosome |
