美国马萨诸塞大学陈医学院Andrei A. Korostelev和Anna B. Loveland共同合作，近期取得重要工作进展。他们研究提出了核糖体激活血管生成素的结构机制。相关研究成果2024年5月8日在线发表于《自然》杂志上。

据介绍，血管生成素是一种RNase A家族蛋白，促进血管生成，并与癌症、神经退行性疾病和表观遗传有关。在细胞应激过程中激活后，血管生成素在反密码子环切割tRNA，导致翻译抑制。然而，分离的血管生成素的催化活性非常低，并且酶激活和tRNA特异性的机制仍不清楚。

研究人员使用生物化学分析和冷冻电镜揭示了这些机制。研究发现，胞质核糖体是长期寻求的血管生成素激活剂。2.8Å分辨率的冷冻电镜结构特征显示，血管生成素结合在80S核糖体的A位点。血管生成素的C末端尾部通过与核糖体的相互作用重新排列，以激活RNase催化中心，使该酶在tRNA切割中的效率提高几个数量级。额外的80S·血管生成素结构捕捉核糖体如何将tRNA底物引导到血管生成素的活性位点，表明核糖体起到特异性因子的作用。

因此，这一研究结果表明，血管生成素被具有空缺a位点的核糖体激活，其丰度在细胞应激期间增加。这些结果可能有助于开发治疗癌症和神经退行性疾病的疗法。

附：英文原文

Title: Structural mechanism of angiogenin activation by the ribosome

Author: Loveland, Anna B., Koh, Cha San, Ganesan, Robin, Jacobson, Allan, Korostelev, Andrei A.

Issue&Volume: 2024-05-08

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- 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 80Sangiogenin 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.

DOI: 10.1038/s41586-024-07508-8

Source: https://www.nature.com/articles/s41586-024-07508-8