Nature2014-06-26 1:41 PM

一种Tet-样蛋白的结构 Structure of a Naegleria Tet-like dioxygenase in complex with 5-methylcytosine DNA

论文摘要 

Tet家族的加双氧酶将5-甲基胞嘧啶(5mC)转化成5-羟甲基胞嘧啶(5hmC)、5-甲酰基胞嘧啶(5fC)和5-羧基胞嘧啶(5caC)。在这项研究中,Xiaodong Cheng及同事从结构上和生化上定性了来自阿米巴鞭毛体Naegleria gruberi的Tet-样蛋白。Naegleria Tet-样蛋白(NgTet1)与哺乳动物Tet蛋白的序列相似性大约为39%,同时也具有相似的生化活性。与含有一个甲基化的CpG点的DNA形成复合物的NgTet1的晶体结构显示,NgTet1利用一个碱基翻转机制来接触5mC。

Abstract 

Cytosine residues in mammalian DNA occur in five forms: cytosine (C), 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). The ten-eleven translocation (Tet) dioxygenases convert 5mC to 5hmC, 5fC and 5caC in three consecutive, Fe(II)- and α-ketoglutarate-dependent oxidation reactions. The Tet family of dioxygenases is widely distributed across the tree of life, including in the heterolobosean amoeboflagellate Naegleria gruberi. The genome of Naegleria encodes homologues of mammalian DNA methyltransferase and Tet proteins. Here we study biochemically and structurally one of the Naegleria Tet-like proteins (NgTet1), which shares significant sequence conservation (approximately 14% identity or 39% similarity) with mammalian Tet1. Like mammalian Tet proteins, NgTet1 acts on 5mC and generates 5hmC, 5fC and 5caC. The crystal structure of NgTet1 in complex with DNA containing a 5mCpG site revealed that NgTet1 uses a base-flipping mechanism to access 5mC. The DNA is contacted from the minor groove and bent towards the major groove. The flipped 5mC is positioned in the active-site pocket with planar stacking contacts, Watson–Crick polar hydrogen bonds and van der Waals interactions specific for 5mC. The sequence conservation between NgTet1 and mammalian Tet1, including residues involved in structural integrity and functional significance, suggests structural conservation across phyla.

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