Structural basis of Spliced Leader RNA recognition by the Trypanosoma brucei cap-binding complex
Abstract Kinetoplastids are a clade of eukaryotic protozoans that include human parasitic pathogens like trypanosomes and Leishmania species. In these organisms, protein-coding genes are transcribed as polycistronic pre-mRNAs, which need to be processed by the coupled action of trans-splicing and po...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55373-w |
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| author | Harald Bernhard Hana Petržílková Barbora Popelářová Kamil Ziemkiewicz Karolina Bartosik Marcin Warmiński Laura Tengo Henri Gröger Luciano G. Dolce Cameron D. Mackereth Ronald Micura Jacek Jemielity Eva Kowalinski |
| author_facet | Harald Bernhard Hana Petržílková Barbora Popelářová Kamil Ziemkiewicz Karolina Bartosik Marcin Warmiński Laura Tengo Henri Gröger Luciano G. Dolce Cameron D. Mackereth Ronald Micura Jacek Jemielity Eva Kowalinski |
| author_sort | Harald Bernhard |
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| description | Abstract Kinetoplastids are a clade of eukaryotic protozoans that include human parasitic pathogens like trypanosomes and Leishmania species. In these organisms, protein-coding genes are transcribed as polycistronic pre-mRNAs, which need to be processed by the coupled action of trans-splicing and polyadenylation to yield monogenic mature mRNAs. During trans-splicing, a universal RNA sequence, the spliced leader RNA (SL RNA) mini-exon, is added to the 5’-end of each mRNA. The 5’-end of this mini-exon carries a hypermethylated cap structure and is bound by a trypanosomatid-specific cap-binding complex (CBC). The function of three of the kinetoplastid CBC subunits is unknown, but an essential role in cap-binding and trans-splicing has been suggested. Here, we report cryo-EM structures that reveal the molecular architecture of the Trypanosoma brucei CBC (TbCBC) complex. We find that TbCBC interacts with two distinct features of the SL RNA. The TbCBP20 subunit interacts with the m7G cap while TbCBP66 recognizes double-stranded portions of the SL RNA. Our findings pave the way for future research on mRNA maturation in kinetoplastids. Moreover, the observed structural similarities and differences between TbCBC and the mammalian cap-binding complex will be crucial for considering the potential of TbCBC as a target for anti-trypanosomatid drug development. |
| format | Article |
| id | doaj-art-2180d541d1cf45a2ba51969327a4fbb2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2180d541d1cf45a2ba51969327a4fbb22025-01-19T12:31:24ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-024-55373-wStructural basis of Spliced Leader RNA recognition by the Trypanosoma brucei cap-binding complexHarald Bernhard0Hana Petržílková1Barbora Popelářová2Kamil Ziemkiewicz3Karolina Bartosik4Marcin Warmiński5Laura Tengo6Henri Gröger7Luciano G. Dolce8Cameron D. Mackereth9Ronald Micura10Jacek Jemielity11Eva Kowalinski12EMBL Grenoble, 71 Avenue des MartyrsEMBL Grenoble, 71 Avenue des MartyrsEMBL Grenoble, 71 Avenue des MartyrsCentre of New Technologies, University of WarsawInstitute of Organic Chemistry, Center for Molecular Biosciences Innsbruck, University of InnsbruckDivision of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of WarsawEMBL Grenoble, 71 Avenue des MartyrsEMBL Grenoble, 71 Avenue des MartyrsEMBL Grenoble, 71 Avenue des MartyrsUniversity of Bordeaux, INSERM, CNRS, ARNA Laboratory, U1212, UMR 5320Institute of Organic Chemistry, Center for Molecular Biosciences Innsbruck, University of InnsbruckCentre of New Technologies, University of WarsawEMBL Grenoble, 71 Avenue des MartyrsAbstract Kinetoplastids are a clade of eukaryotic protozoans that include human parasitic pathogens like trypanosomes and Leishmania species. In these organisms, protein-coding genes are transcribed as polycistronic pre-mRNAs, which need to be processed by the coupled action of trans-splicing and polyadenylation to yield monogenic mature mRNAs. During trans-splicing, a universal RNA sequence, the spliced leader RNA (SL RNA) mini-exon, is added to the 5’-end of each mRNA. The 5’-end of this mini-exon carries a hypermethylated cap structure and is bound by a trypanosomatid-specific cap-binding complex (CBC). The function of three of the kinetoplastid CBC subunits is unknown, but an essential role in cap-binding and trans-splicing has been suggested. Here, we report cryo-EM structures that reveal the molecular architecture of the Trypanosoma brucei CBC (TbCBC) complex. We find that TbCBC interacts with two distinct features of the SL RNA. The TbCBP20 subunit interacts with the m7G cap while TbCBP66 recognizes double-stranded portions of the SL RNA. Our findings pave the way for future research on mRNA maturation in kinetoplastids. Moreover, the observed structural similarities and differences between TbCBC and the mammalian cap-binding complex will be crucial for considering the potential of TbCBC as a target for anti-trypanosomatid drug development.https://doi.org/10.1038/s41467-024-55373-w |
| spellingShingle | Harald Bernhard Hana Petržílková Barbora Popelářová Kamil Ziemkiewicz Karolina Bartosik Marcin Warmiński Laura Tengo Henri Gröger Luciano G. Dolce Cameron D. Mackereth Ronald Micura Jacek Jemielity Eva Kowalinski Structural basis of Spliced Leader RNA recognition by the Trypanosoma brucei cap-binding complex Nature Communications |
| title | Structural basis of Spliced Leader RNA recognition by the Trypanosoma brucei cap-binding complex |
| title_full | Structural basis of Spliced Leader RNA recognition by the Trypanosoma brucei cap-binding complex |
| title_fullStr | Structural basis of Spliced Leader RNA recognition by the Trypanosoma brucei cap-binding complex |
| title_full_unstemmed | Structural basis of Spliced Leader RNA recognition by the Trypanosoma brucei cap-binding complex |
| title_short | Structural basis of Spliced Leader RNA recognition by the Trypanosoma brucei cap-binding complex |
| title_sort | structural basis of spliced leader rna recognition by the trypanosoma brucei cap binding complex |
| url | https://doi.org/10.1038/s41467-024-55373-w |
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