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TitleStructural mechanism of angiogenin activation by the ribosome.
Journal, issue, pagesNature, Vol. 630, Issue 8017, Page 769-776, Year 2024
Publish dateMay 8, 2024
AuthorsAnna B Loveland / Cha San Koh / Robin Ganesan / Allan Jacobson / Andrei A Korostelev /
PubMed AbstractAngiogenin, an RNase-A-family protein, promotes angiogenesis and has been implicated in cancer, neurodegenerative diseases and epigenetic inheritance. After activation during cellular stress, ...Angiogenin, an RNase-A-family protein, promotes angiogenesis and has been implicated in cancer, neurodegenerative diseases and epigenetic inheritance. After activation during cellular stress, angiogenin cleaves tRNAs at the anticodon loop, resulting in translation repression. However, the catalytic activity of isolated angiogenin is very low, and the mechanisms of the enzyme activation and tRNA specificity have remained a puzzle. Here we identify these mechanisms using biochemical assays and cryogenic electron microscopy (cryo-EM). Our study reveals that the cytosolic ribosome is the activator of angiogenin. A 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 centre, making the enzyme several orders of magnitude more efficient in tRNA cleavage. Additional 80S-angiogenin structures capture how tRNA substrate is directed by the ribosome into 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, the abundance of which increases during cellular stress. These results may facilitate the development of therapeutics to treat cancer and neurodegenerative diseases.
External linksNature / PubMed:38718836
MethodsEM (single particle)
Resolution2.8 - 3.9 Å
Structure data

EMDB-44457: 80S ribosome with angiogenin and ternary complex in rabbit reticulocyte lysates
Method: EM (single particle) / Resolution: 3.36 Å

EMDB-44458: 80S ribosome with angiogenin, in vitro assembled complex without substrate tRNA
Method: EM (single particle) / Resolution: 3.04 Å

EMDB-44459: 80S ribosome with H13A angiogenin
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-44460: 80S ribosome with H13A angiogenin and tRNA
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-44461, PDB-9bdl:
80S ribosome with angiogenin
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-44463, PDB-9bdn:
80S ribosome with angiogenin and tRNAAla
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-44464, PDB-9bdp:
80S ribosome bound with angiogenin and complex of eEF1A and Ala-tRNAAla
Method: EM (single particle) / Resolution: 3.7 Å

Source
  • oryctolagus cuniculus (rabbit)
  • homo sapiens (human)
  • escherichia coli (E. coli)
  • saccharomyces cerevisiae (brewer's yeast)
  • escherichia coli k-12 (bacteria)
KeywordsRIBOSOME / Angiogenin / RNase

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