9BDP

80S ribosome bound with angiogenin and complex of eEF1A and Ala-tRNAAla

This is a non-PDB format compatible entry.

Summary for 9BDP

• Entry DOI: 10.2210/pdb9bdp/pdb
• Related: 9BDL 9BDN
• EMDB information: 44457 44458 44459 44460 44461 44463 44464
• Descriptor: 18S rRNA, 60S ribosomal protein L7, Large ribosomal subunit protein eL8, ... (85 entities in total)
• Functional Keywords: angiogenin, rnase, ribosome
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 86
• Total formula weight: 3385481.16

Authors

Loveland, A.B.,Korostelev, A.A. (deposition date: 2024-04-12, release date: 2024-07-24)

Primary citation

Loveland, A.B.,Koh, C.S.,Ganesan, R.,Jacobson, A.,Korostelev, A.A.
Structural mechanism of angiogenin activation by the ribosome.
Nature, 630:769-776, 2024

PubMed Abstract: 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.

PubMed: 38718836
DOI: 10.1038/s41586-024-07508-8

Experimental method

ELECTRON MICROSCOPY (3.7 Å)