Geometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding
Abstract Accurate protein synthesis is determined by the two-subunit ribosome’s capacity to selectively incorporate cognate aminoacyl-tRNA for each mRNA codon. The molecular basis of tRNA selection accuracy, and how fidelity can be affected by antibiotics, remains incompletely understood. Using mole...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40404-9 |
| _version_ | 1827709699181510656 |
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| author | Dylan Girodat Hans-Joachim Wieden Scott C. Blanchard Karissa Y. Sanbonmatsu |
| author_facet | Dylan Girodat Hans-Joachim Wieden Scott C. Blanchard Karissa Y. Sanbonmatsu |
| author_sort | Dylan Girodat |
| collection | DOAJ |
| description | Abstract Accurate protein synthesis is determined by the two-subunit ribosome’s capacity to selectively incorporate cognate aminoacyl-tRNA for each mRNA codon. The molecular basis of tRNA selection accuracy, and how fidelity can be affected by antibiotics, remains incompletely understood. Using molecular simulations, we find that cognate and near-cognate tRNAs delivered to the ribosome by Elongation Factor Tu (EF-Tu) can follow divergent pathways of motion into the ribosome during both initial selection and proofreading. Consequently, cognate aa-tRNAs follow pathways aligned with the catalytic GTPase and peptidyltransferase centers of the large subunit, while near-cognate aa-tRNAs follow pathways that are misaligned. These findings suggest that differences in mRNA codon-tRNA anticodon interactions within the small subunit decoding center, where codon-anticodon interactions occur, are geometrically amplified over distance, as a result of this site’s physical separation from the large ribosomal subunit catalytic centers. These insights posit that the physical size of both tRNA and ribosome are key determinants of the tRNA selection fidelity mechanism. |
| first_indexed | 2024-03-10T17:25:33Z |
| format | Article |
| id | doaj.art-a5e0703efe69456b8f8e549d1ab39eb7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:25:33Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-a5e0703efe69456b8f8e549d1ab39eb72023-11-20T10:11:23ZengNature PortfolioNature Communications2041-17232023-09-0114111510.1038/s41467-023-40404-9Geometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decodingDylan Girodat0Hans-Joachim Wieden1Scott C. Blanchard2Karissa Y. Sanbonmatsu3Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National LaboratoryDepartment of Microbiology, University of ManitobaDepartment of Structural Biology, St. Jude Children’s Research HospitalTheoretical Biology and Biophysics, Theoretical Division, Los Alamos National LaboratoryAbstract Accurate protein synthesis is determined by the two-subunit ribosome’s capacity to selectively incorporate cognate aminoacyl-tRNA for each mRNA codon. The molecular basis of tRNA selection accuracy, and how fidelity can be affected by antibiotics, remains incompletely understood. Using molecular simulations, we find that cognate and near-cognate tRNAs delivered to the ribosome by Elongation Factor Tu (EF-Tu) can follow divergent pathways of motion into the ribosome during both initial selection and proofreading. Consequently, cognate aa-tRNAs follow pathways aligned with the catalytic GTPase and peptidyltransferase centers of the large subunit, while near-cognate aa-tRNAs follow pathways that are misaligned. These findings suggest that differences in mRNA codon-tRNA anticodon interactions within the small subunit decoding center, where codon-anticodon interactions occur, are geometrically amplified over distance, as a result of this site’s physical separation from the large ribosomal subunit catalytic centers. These insights posit that the physical size of both tRNA and ribosome are key determinants of the tRNA selection fidelity mechanism.https://doi.org/10.1038/s41467-023-40404-9 |
| spellingShingle | Dylan Girodat Hans-Joachim Wieden Scott C. Blanchard Karissa Y. Sanbonmatsu Geometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding Nature Communications |
| title | Geometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding |
| title_full | Geometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding |
| title_fullStr | Geometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding |
| title_full_unstemmed | Geometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding |
| title_short | Geometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding |
| title_sort | geometric alignment of aminoacyl trna relative to catalytic centers of the ribosome underpins accurate mrna decoding |
| url | https://doi.org/10.1038/s41467-023-40404-9 |
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