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

Luciano G. Dolce, Aubree A. Zimmer, Laura Tengo, Félix Weis, Mary Anne T. Rubio, Juan D. Alfonzo and Eva Kowalinski ()
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Luciano G. Dolce: EMBL Grenoble
Aubree A. Zimmer: The Ohio State University
Laura Tengo: EMBL Grenoble
Félix Weis: EMBL Heidelberg, Structural and Computational Biology Unit
Mary Anne T. Rubio: The Ohio State University
Juan D. Alfonzo: The Ohio State University
Eva Kowalinski: EMBL Grenoble

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract The essential deamination of adenosine A34 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 A34 deamination evolved, shaped the genetic code, and directly impacts the eukaryotic proteome.

Date: 2022
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DOI: 10.1038/s41467-022-34441-z

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