Structural basis of 5′ splice site recognition by the minor spliceosome
Open accessPublished version of a preprint
Abstract
The minor spliceosome catalyzes excision of U12-dependent introns from precursors of eukaryotic messenger RNAs (pre-mRNAs). This process is critical for many cellular functions, but the underlying molecular mechanisms remain elusive. Here, we report a cryoelectron microscopy (cryo-EM) reconstruction of the 13-subunit human U11 small nuclear ribonucleoprotein particle (snRNP) complex in apo and substrate-bound forms, revealing the architecture of the U11 small nuclear RNA (snRNA), five minor spliceosome-specific factors, and the mechanism of the U12-type 5' splice site (5'SS) recognition. SNRNP25 and SNRNP35 specifically recognize U11 snRNA, while PDCD7 bridges SNRNP25 and SNRNP48, located at the distal ends of the particle. SNRNP48 and ZMAT5 are positioned near the 5' end of U11 snRNA and stabilize binding of the incoming 5'SS. Recognition of the U12-type 5'SS is achieved through base-pairing to the 5' end of the U11 snRNA and unexpected, non-canonical base-triple interactions with the U11 snRNA stem-loop 3. Our structures provide mechanistic insights into U12-dependent intron recognition and the evolution of the splicing machinery.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Spliceosome Structure and Function
Will, C. L., & Luhrmann, R. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a003707 · Cited by 1,829 · see citing works
A day in the life of the spliceosome
Matera, A. G., & Wang, Z. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3742 · Cited by 1,074 · see citing works
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- Authors
- Zhao, J., Peter, D., Brandina, I., Liu, X., & Galej, W. P.
- Affiliations
- European Molecular Biology Laboratory (FR)
- Corresponding author
- Galej, Wojciech P.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2025-02
- Volume
- 85
- Issue
- 3
- Pages
- 652-664.e4
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W4406319762
- Cited by
- 15
- References
- 3
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 1
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- European Molecular Biology Laboratory
- European Commission (HORIZON2020)
- European Synchrotron Radiation Facility
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- minor spliceosome, 5' splice site recognition, pre-mRNA splicing, spliceosome structure
- MeSH terms
- Binding Sites, HeLa Cells, Humans, Introns, Models, Molecular, Nucleic Acid Conformation, Protein Binding, RNA Precursors, RNA Splicing, RNA, Small Nuclear, Spliceosomes, Ribonucleoproteins, Small Nuclear, Cryoelectron Microscopy, RNA Splice Sites
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