血管生长素
核糖核酸酶P
核糖体
转移RNA
核糖核酸酶
细胞生物学
生物
蛋白质生物合成
化学
翻译(生物学)
内部核糖体进入位点
生物化学
信使核糖核酸
核糖核酸
遗传学
血管生成
基因
作者
A.B. Loveland,Cha San Koh,Robin Ganesan,Allan Jacobson,А.A. Коростелев
标识
DOI:10.1101/2023.12.11.570495
摘要
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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