Abstract
Angiogenin, an RNase A-family protein, promotes angiogenesis and has been implicated in cancer, neurodegenerative diseases, and epigenetic inheritance 1-10. Upon activation during cellular stress, angiogenin cleaves tRNAs at the anticodon loop, resulting in translation repression 11-15. The catalytic activity of isolated angiogenin, however, is very low, and the mechanisms of the enzyme activation and tRNA specificity have remained a puzzle 3,16-23. 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 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, whose abundance increases during cellular stress24-27. These results may facilitate the development of therapeutics to treat cancer and neurodegenerative diseases.
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Supplementary Information
This file contains the Supplementary Discussion, full descriptions for Supplementary Videos 1 and 2, Supplementary Fig. 1 and Supplementary references.
Supplementary Video 1
Cryo-EM maps and rigid-body fits of the subclasses of 80S•angiogenin•tRNAAla show different positions of tRNA (green) and P stalk (cyan, upper left corner) relative to angiogenin (magenta). This flexible tethering of the tRNA may allow cleavage at different anticodon positions on various tRNA species. The cryo-EM maps were low-pass filtered to 6 Å and are shown at 2.5 σ.
Supplementary Video 2
Cryo-EM maps and rigid-body fits of the subclasses of 80S•angiogenin•tRNAAla show different positions of tRNA (green) and P stalk (cyan, upper left corner) relative to the 60S subunit’s GTPase activation center. The cryo-EM maps were low-pass filtered to 6 Å and are shown at 2.5 σ.
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Loveland, A.B., Koh, C.S., Ganesan, R. et al. Structural mechanism of angiogenin activation by the ribosome. Nature (2024). https://doi.org/10.1038/s41586-024-07508-8
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DOI: https://doi.org/10.1038/s41586-024-07508-8
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