The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112
The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112
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DOI：
10.1093/nar/gkz619
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发表时间：
2019-09-05
影响因子：
14.9
通讯作者：
Lafontaine, Denis L. J.
中科院分区：
文献类型：
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作者：
Nhan Van Tran;Ernst, Felix G. M.;Lafontaine, Denis L. J.
N6-甲基腺苷（m（6）A）最近被发现在信使RNA上大量存在，并被证明调节mRNA代谢的大多数步骤。几种重要的m（6）A甲基转移酶已经在功能和结构上被描述，但是负责在人类核糖体的每个亚基上在功能上重要的位点安装一个m（6）A残基的酶已经超过30年没有被鉴定。在此，我们鉴定了胃L5为负责18 S rRNA m（6）A修饰的酶，并确认ZCCHC 4为28 S rRNA修饰酶。我们发现，胃L5必须与TRMT 112（一种已知的甲基转移酶激活剂）形成异二聚体复合物，以获得细胞中的代谢稳定性。我们首次获得了胃L5-TRMT 112的原子分辨率结构，支持其RNA结合模式与其他m（6）A RNA甲基转移酶明显不同。基于与DNA甲基转移酶的相似性，我们提出胃L5-TRMT 112通过从双链核酸中挤出待修饰的腺苷而起作用。
N6-methyladenosine (m(6)A) has recently been found abundantly on messenger RNA and shown to regulate most steps of mRNA metabolism. Several important m(6)A methyltransferases have been described functionally and structurally, but the enzymes responsible for installing one m(6)A residue on each subunit of human ribosomes at functionally important sites have eluded identification for over 30 years. Here, we identify METTL5 as the enzyme responsible for 18S rRNA m(6)A modification and confirm ZCCHC4 as the 28S rRNA modification enzyme. We show that METTL5 must form a heterodimeric complex with TRMT112, a known methyltransferase activator, to gain metabolic stability in cells. We provide the first atomic resolution structure of METTL5-TRMT112, supporting that its RNA-binding mode differs distinctly from that of other m(6)A RNA methyltransferases. On the basis of similarities with a DNA methyltransferase, we propose that METTL5-TRMT112 acts by extruding the adenosine to be modified from a double-stranded nucleic acid.