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Structural basis for sequence-independent substrate selection by eukaryotic wobble base tRNA deaminase ADAT2/3

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Dolce, Luciano G., Zimmer, Aubree A., Tengo, Laura, Weis, Félix, Rubio, Mary Anne T., Alfonzo, Juan D., Kowalinski, Eva·2022·Nature Communications
DOI 10.1038/s41467-022-34441-zPMC PMC9643335

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Abstract

The essential deamination of adenosine A 34 to inosine at the wobble base is the individual tRNA modification with the greatest effects on mRNA decoding, empowering a single tRNA to translate three different codons. To date, many aspects of how eukaryotic deaminases specifically select their multiple substrates remain unclear. Here, using cryo-EM, we present the structure of a eukaryotic ADAT2/3 deaminase bound to a full-length tRNA, revealing that the enzyme distorts the anticodon loop, but in contrast to the bacterial enzymes, selects its substrate via sequence-independent contacts of eukaryote-acquired flexible or intrinsically unfolded motifs distal from the conserved catalytic core. A gating mechanism for substrate entry to the active site is identified. Our multi-step tRNA recognition model yields insights into how RNA editing by A 34 deamination evolved, shaped the genetic code, and directly impacts the eukaryotic proteome.

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Metadata

Authors
Dolce, L. G., Zimmer, A. A., Tengo, L., Weis, F., Rubio, M. A. T., Alfonzo, J. D., & Kowalinski, E.
Affiliations
  • European Molecular Biology Laboratory (FR)
  • The Ohio State University (US)
  • European Molecular Biology Laboratory (DE)
Corresponding author
Kowalinski, Eva
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-11-08
Volume
13
Issue
1
Pages
6737-6737
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-34441-z
PMC
PMC9643335
OpenAlex
W4308541754
Cited by
27
References
2
Citations by year
2026: 8 · 2025: 7 · 2024: 8 · 2023: 4
FWCI
1.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Foundation for the National Institutes of Health (GM084065-11)
  • Agence Nationale de la Recherche (ANR-20-CE11-0016)
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 modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
tRNA modification, genetic code, cryo-EM structure
MeSH terms
Adenosine Deaminase, Anticodon, Inosine, RNA, Transfer, Eukaryota

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