Structural basis for pre-tRNA recognition and processing by the human tRNA splicing endonuclease complex
Open accessPublished version of a preprint
Abstract
Throughout bacteria, archaea and eukarya, certain tRNA transcripts contain introns. Pre-tRNAs with introns require splicing to form the mature anticodon stem loop. In eukaryotes, tRNA splicing is initiated by the heterotetrameric tRNA splicing endonuclease (TSEN) complex. All TSEN subunits are essential, and mutations within the complex are associated with a family of neurodevelopmental disorders known as pontocerebellar hypoplasia (PCH). Here, we report cryo-electron microscopy structures of the human TSEN-pre-tRNA complex. These structures reveal the overall architecture of the complex and the extensive tRNA binding interfaces. The structures share homology with archaeal TSENs but contain additional features important for pre-tRNA recognition. The TSEN54 subunit functions as a pivotal scaffold for the pre-tRNA and the two endonuclease subunits. Finally, the TSEN structures enable visualization of the molecular environments of PCH-causing missense mutations, providing insight into the mechanism of pre-tRNA splicing and PCH.
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References 54 · Cited by 30
- Authors
- Hayne, C. K., Butay, K. J. U., Stewart, Z. D., Krahn, J. M., Perera, L., Williams, J. G., Petrovitch, R. M., Deterding, L. J., Matera, A. G., Borgnia, M. J., & Stanley, R. E.
- Affiliations
- National Institutes of Health (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Hayne, Cassandra K.
- Stanley, Robin E.
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2023-05-25
- Volume
- 30
- Issue
- 6
- Pages
- 824-833
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC10627149
- OpenAlex
- W4378212328
- Cited by
- 30
- References
- 54
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 10 · 2023: 8
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-01-09)
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (1zices103206-08, 1zices102488-04, ZIC ES102488, ZIC ES103206)
- National Cancer Institute
- National Institute of General Medical Sciences (1K99-GM143534, K99GM143573, R35GM136435, R00GM143534)
- National Institute of Environmental Health Sciences (Z01ES102488, Z01ES102487, Z01ES043010, ZICES102487, ZIAES103247, ZICES103326)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- tRNA splicing endonuclease, tRNA introns, pontocerebellar hypoplasia, neurodevelopmental disorders, tRNA binding, cryo-EM structure, missense mutations, anticodon stem-loop
- MeSH terms
- Archaea, Endoribonucleases, Humans, Introns, Nucleic Acid Conformation, RNA Precursors, RNA Splicing, RNA, Transfer, Cryoelectron Microscopy, Eukaryota
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