Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA

Kuhle, Bernhard; Hirschi, Marscha; Doerfel, Lili K.; Lander, Gabriel C.; Schimmel, Paul

doi:10.1038/s41467-022-32544-1

Cited by 16 publications

(30 citation statements)

References 74 publications

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“…Most tRNAs encoded in human mitochondria are highly degenerate, and differ significantly in sequence, structure, and stability from canonical tRNAs encoded in the nucleus 28,63 . Most notably, mt-tRNAs often lack universally conserved tRNA structural features that are used by many tRNA-processing factors to recognize nu-tRNAs 23,28,35,40 . ELAC2 catalyzes tRNA 3'-processing both in the nucleus and mitochondria 31,42,49 , and thus must recognize pre-tRNAs from both compartments.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of human nuclear and mitochondrial tRNA 3’-processing

Bhatta,

Kuhle,

et al. 2024

Preprint

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Eukaryotic transfer RNA (tRNA) precursors undergo sequential processing steps to become mature tRNAs. In humans, ELAC2 carries out 3 prime-end processing of both nucleus-encoded (nu-tRNAs) and mitochondria-encoded tRNAs (mt-tRNAs). ELAC2 is self-sufficient for processing of nu-tRNAs, but requires TRMT10C and SDR5C1 to process most mt-tRNAs. Here, we show that TRMT10C-SDR5C1 specifically facilitate processing of structurally degenerate mt-tRNAs lacking the canonical elbow. Structures of ELAC2 in complex with TRMT10C, SDR5C1 and two divergent mt-tRNA substrates reveal two distinct mechanisms of pre-tRNA recognition. While canonical nu-tRNAs and mt-tRNAs are recognized by direct ELAC2-RNA interactions, processing of non-canonical mt-tRNAs depends on protein-protein interactions between ELAC2 and TRMT10C. These results provide the molecular basis for tRNA 3 prime-processing in both the nucleus and mitochondria and explain the organelle-specific requirement for additional factors. Moreover, they suggest that TRMT10C-SDR5C1 evolved as a mitochondrial tRNA maturation platform to compensate for the structural erosion of mt-tRNAs in bilaterian animals.

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Section: Discussionmentioning

confidence: 99%

Molecular basis of human nuclear and mitochondrial tRNA 3’-processing

Bhatta,

Kuhle,

et al. 2024

Preprint

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“…When preorphan GlyRS evolved to more accurately and effectively capture tRNA Gly by integrating an ABD, the ABD was not obtained from other class IIa aaRSs but from ArgRS, because the ABD of ArgRS has multiple specific interactions with C35 of tRNA Arg . For other tRNAs with C at position 35, their corresponding aaRSs recognize tRNA either through the shape of the cognate tRNA [e.g., seryl-tRNA synthetase (SerRS) and cysteinyl-tRNA synthetase (CysRS)] or by forming more interactions with another nucleotide in the anticodon loop [e.g., trytophanyl-tRNA synthetase (TrpRS)] ( 29 , 54 – 56 ).…”

Section: Discussionmentioning

confidence: 99%

The binding mode of orphan glycyl-tRNA synthetase with tRNA supports the synthetase classification and reveals large domain movements

Han

Luo

et al. 2023

Sci. Adv.

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As a class of essential enzymes in protein translation, aminoacyl–transfer RNA (tRNA) synthetases (aaRSs) are organized into two classes of 10 enzymes each, based on two conserved active site architectures. The (αβ) 2 glycyl-tRNA synthetase (GlyRS) in many bacteria is an orphan aaRS whose sequence and unprecedented X-shaped structure are distinct from those of all other aaRSs, including many other bacterial and all eukaryotic GlyRSs. Here, we report a cocrystal structure to elucidate how the orphan GlyRS kingdom specifically recognizes its substrate tRNA. This structure is sharply different from those of other aaRS-tRNA complexes but conforms to the clash-free, cross-class aaRS-tRNA docking found with conventional structures and reinforces the class-reconstruction paradigm. In addition, noteworthy, the X shape of orphan GlyRS is condensed with the largest known spatial rearrangement needed by aaRSs to capture tRNAs, which suggests potential nonactive site targets for aaRS-directed antibiotics, instead of less differentiated hard-to-drug active site locations.

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“…These data suggest a more critical role of the C-terminal tail for binding hmtRNA Ser (AGY) in catalysis, in accordance with the previously reported results ( 19 ). Indeed, a very recent study has reported the cyro-EM structure of SARS2-tRNA Ser (AGY), which clearly shows that the very C-terminus provides an important interaction site for binding the T-stem sugar-phosphate backbone of tRNA Ser (AGY) ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease

Zhang

Zheng

et al. 2022

Nucleic Acids Research

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Mitochondrial translation is of high significance for cellular energy homeostasis. Aminoacyl-tRNA synthetases (aaRSs) are crucial translational components. Mitochondrial aaRS variants cause various human diseases. However, the pathogenesis of the vast majority of these diseases remains unknown. Here, we identified two novel SARS2 (encoding mitochondrial seryl-tRNA synthetase) variants that cause a multisystem disorder. c.654–14T > A mutation induced mRNA mis-splicing, generating a peptide insertion in the active site; c.1519dupC swapped a critical tRNA-binding motif in the C-terminus due to stop codon readthrough. Both mutants exhibited severely diminished tRNA binding and aminoacylation capacities. A marked reduction in mitochondrial tRNASer(AGY) was observed due to RNA degradation in patient-derived induced pluripotent stem cells (iPSCs), causing impaired translation and comprehensive mitochondrial function deficiencies. These impairments were efficiently rescued by wild-type SARS2 overexpression. Either mutation caused early embryonic fatality in mice. Heterozygous mice displayed reduced muscle tissue-specific levels of tRNASers. Our findings elucidated the biochemical and cellular consequences of impaired translation mediated by SARS2, suggesting that reduced abundance of tRNASer(AGY) is a key determinant for development of SARS2-related diseases.

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Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA

Cited by 16 publications

References 74 publications

Molecular basis of human nuclear and mitochondrial tRNA 3’-processing

Molecular basis of human nuclear and mitochondrial tRNA 3’-processing

The binding mode of orphan glycyl-tRNA synthetase with tRNA supports the synthetase classification and reveals large domain movements

Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease

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