Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases.
Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases.
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DOI：
10.1016/j.molcel.2016.05.041
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发表时间：
2016-07-21
期刊：
影响因子：
16
通讯作者：
Nam Y
中科院分区：
文献类型：
--
作者：
Wang P;Doxtader KA;Nam Y
N6-甲基腺苷（m6 A）是一种常见的，可逆的功能RNA的化学修饰，是生物学中的重要事件。核心m6 A编写者是Mettl 3和Mettl 14，它们都含有甲基转移酶结构域。Mettl 3和Mettl 14如何合作催化腺苷甲基化仍然是难以捉摸的。我们目前的晶体结构的复杂的Mettl 3/Mettl 14甲基转移酶结构域的载脂蛋白的形式，以及结合S-腺苷甲硫氨酸（SAM）或S-腺苷高半胱氨酸（SAH）的催化位点。我们确定甲基转移酶结构域的异二聚体复合物与CCCH基序相结合构成了在体外创建m6 A修饰所需的最低限度的区域。我们还表明，Mettl 3是催化活性的亚基，而Mettl 14起着关键的结构作用的基板识别。我们的模型为为什么Mettl 3和Mettl 14的某些突变导致甲基转移酶复合物的功能受损提供了分子解释。Wang等人揭示了Mettl 3/Mettl 14复合物的晶体结构。广泛的分子间接触使Mettl 3和Mettl 14能够协同工作。Mettl 3是催化亚基，Mettl 14通过变构和识别RNA底物来激活Mettl 3。他们解释了为什么某些突变，包括那些参与癌症的突变，会影响RNA甲基化。
N6-methyladenosine (m6A) is a prevalent, reversible chemical modification of functional RNAs, and is important for central events in biology. The core m6A writers are Mettl3 and Mettl14, which both contain methyltransferase domains. How Mettl3 and Mettl14 cooperate to catalyze methylation of adenosines has remained elusive. We present crystal structures of the complex of Mettl3/Mettl14 methyltransferase domains in apo form as well as with bound S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) in the catalytic site. We determine that the heterodimeric complex of methyltransferase domains, combined with CCCH motifs constitute the minimally required regions for creating m6A modifications in vitro. We also show that Mettl3 is the catalytically active subunit while Mettl14 plays a structural role critical for substrate recognition. Our model provides a molecular explanation for why certain mutations of Mettl3 and Mettl14 lead to impaired function of the methyltransferase complex. Wang et al. reveal crystal structures of Mettl3/Mettl14 complexes. Extensive intermolecular contact enables Mettl3 and Mettl14 to work cooperatively. Mettl3 is the catalytic subunit, and Mettl14 activates Mettl3 via allostery and recognition of RNA substrates. They explain why certain mutations including those involved in cancer affect RNA methylation.