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Structural mechanism of angiogenin activation by the ribosome

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Loveland, Anna B., Koh, Cha San, Ganesan, Robin, Jacobson, Allan, Korostelev, Andrei A.·2023·Nature
DOI 10.1101/2023.12.11.570495PMC PMC11912008

Preprint — published as 10.1038/s41586-024-07508-8

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Abstract

Angiogenin, an RNase A-family protein, promotes angiogenesis and has been implicated in cancer, neurodegenerative diseases, and epigenetic inheritance. Upon activation during cellular stress, angiogenin cleaves tRNAs at the anticodon loop, producing nicked tRNA (also known as tRNA halves, tiRNAs or tsRNAs) and resulting in translation repression. The catalytic activity of isolated angiogenin, however, is very low, and the mechanisms of the enzyme activation and tRNA specificity have remained a puzzle. Here, we uncover these mechanisms using biochemical assays and cryogenic electron microscopy. Our work reveals that the cytosolic ribosome is the long-sought activator of angiogenin. A 2.8-Å resolution cryo-EM structure features angiogenin bound in the A site of the 80S ribosome. The C-terminal tail of angiogenin is rearranged by interactions with the ribosome to activate the RNase catalytic center, making the enzyme several orders of magnitude more efficient in tRNA cleavage. Additional 80S•angiogenin structures capture how the tRNA substrate is directed by the ribosome next to angiogenin’s active site, demonstrating that the ribosome acts as the specificity factor. Our findings therefore suggest that angiogenin is activated by ribosomes with a vacant A site, whose abundance increases during cellular stresses.

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Metadata

Authors
Loveland, A. B., Koh, C. S., Ganesan, R., Jacobson, A., & Korostelev, A. A.
Affiliations
University of Massachusetts Chan Medical School (US)
Corresponding author
  • Loveland, Anna B.
  • Korostelev, Andrei A.
ORCID
Venue
Nature
Publisher
openRxiv
Published
2023-12-11
Volume
630
Issue
8017
Pages
769-776
ISSN
0028-0836 (ISSN-L)
DOI
10.1101/2023.12.11.570495
PMC
PMC11912008
OpenAlex
W4396732525
Cited by
51
References
1
Citations by year
2026: 20 · 2025: 19 · 2024: 12
FWCI
6.92
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health
  • University of Massachusetts Medical School
  • National Institute of General Medical Sciences (R35GM122468, R35GM148277, R35GM127094)
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 › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
Keywords
angiogenin, ribosome, enzyme activation, tRNA cleavage, anticodon loop, 80S ribosome, A-site, C-terminal tail, translation repression, cellular stress, tRNA specificity
MeSH terms
Anticodon, Binding Sites, Cytosol, Enzyme Activation, Humans, Models, Molecular, Ribonuclease, Pancreatic, Ribosomes, RNA, Transfer, Stress, Physiological, Substrate Specificity, Catalytic Domain, Cryoelectron Microscopy, RNA Cleavage

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