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LARP1在受抑制的复合物中与核糖体和TOP mRNA结合。

LARP1 binds ribosomes and TOP mRNAs in repressed complexes.

作者信息

Saba James A, Huang Zixuan, Schole Kate L, Ye Xianwen, Bhatt Shrey D, Li Yi, Timp Winston, Cheng Jingdong, Green Rachel

机构信息

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

出版信息

EMBO J. 2024 Dec;43(24):6555-6572. doi: 10.1038/s44318-024-00294-z. Epub 2024 Nov 12.

DOI:10.1038/s44318-024-00294-z
PMID:39533057
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11649897/
Abstract

Terminal oligopyrimidine motif-containing mRNAs (TOPs) encode all ribosomal proteins in mammals and are regulated to tune ribosome synthesis to cell state. Previous studies have implicated LARP1 in 40S- or 80S-ribosome complexes that are thought to repress and stabilize TOPs. However, a molecular understanding of how LARP1 and TOPs interact with these ribosome complexes is lacking. Here, we show that LARP1 directly binds non-translating ribosomal subunits. Cryo-EM structures reveal a previously uncharacterized domain of LARP1 bound to and occluding the mRNA channel of the 40S subunit. Increased availability of free ribosomal subunits downstream of various stresses promote 60S joining at the same interface to form LARP1-80S complexes. Simultaneously, LARP1 engages the TOP via its previously characterized La/PAM2 and DM15 domains. Contrary to expectations, ribosome binding within these complexes is not required for LARP1-mediated TOP repression or stabilization, two canonical LARP1 functions. Together, this work provides molecular insight into how LARP1 directly binds ribosomal subunits and challenges existing models describing the function of repressed LARP1-40S/80S-TOP complexes.

摘要

含末端寡嘧啶基序的mRNA（TOPs）编码哺乳动物中的所有核糖体蛋白，并受到调控以根据细胞状态调节核糖体合成。先前的研究表明LARP1存在于40S或80S核糖体复合物中，这些复合物被认为可抑制并稳定TOPs。然而，目前尚缺乏对LARP1和TOPs如何与这些核糖体复合物相互作用的分子层面的理解。在此，我们表明LARP1直接结合非翻译核糖体亚基。冷冻电镜结构揭示了LARP1一个以前未被表征的结构域，它与40S亚基的mRNA通道结合并将其封闭。各种应激下游游离核糖体亚基的可用性增加，促进60S在同一界面处结合形成LARP1 - 80S复合物。同时，LARP1通过其先前已被表征的La/PAM2和DM15结构域与TOP结合。与预期相反，LARP1介导的TOP抑制或稳定这两个典型的LARP1功能并不需要这些复合物内的核糖体结合。总之，这项工作提供了关于LARP1如何直接结合核糖体亚基的分子见解，并挑战了描述受抑制的LARP1 - 40S/80S - TOP复合物功能的现有模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/ac11046b08c1/44318_2024_294_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/5d9f37e4e920/44318_2024_294_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/1b0653e3ca75/44318_2024_294_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/f0087b0216af/44318_2024_294_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/4b63bf80dd50/44318_2024_294_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/e73bac710d89/44318_2024_294_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/ac11046b08c1/44318_2024_294_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/5d9f37e4e920/44318_2024_294_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/1b0653e3ca75/44318_2024_294_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/f0087b0216af/44318_2024_294_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/4b63bf80dd50/44318_2024_294_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/e73bac710d89/44318_2024_294_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8773/11649897/ac11046b08c1/44318_2024_294_Fig6_HTML.jpg

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