Provenance of SET-Domain Histone Methyltransferases Through Duplication of a Simple Structural Unit
Provenance of SET-Domain Histone Methyltransferases Through Duplication of a Simple Structural Unit
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DOI：
10.4161/cc.2.4.419
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发表时间：
2003-01-01
期刊：
影响因子：
4.3
通讯作者：
Iyer, Lakshminarayan M.
中科院分区：
文献类型：
--
作者：
Aravind, L.;Iyer, Lakshminarayan M.
SET结构域是蛋白质赖氨酸甲基转移酶，其甲基化不同的蛋白质，如组蛋白、Rubisco和细胞色素C。特别是，它们在真核染色质的动力学中起重要作用，并存在于几种染色质相关蛋白中。最近，几个SET结构域的结构已经得到解决，它们包含一个保守的折叠，这是不相关的先前表征的甲基转移酶，具有罗斯曼折叠或SPOUT结构域。SET结构域的系统发育和系统谱系分析表明，它是真核生物谱系的进化“发明”，并有次级侧向转移到细菌中。我们发现，保守的N-和C-末端区域，其中包括核心桶样模块的SET域，是一个简单的3-链单位的对称重复。此外，两个对称排列的重复序列有助于SET结构域的两个底物的结合位点。这表明SET结构域是由这个3链单元的祖先二聚体产生的，每个单元可能起着一般配体结合结构的作用。两个重复单元之间的分歧似乎是由于它们与插入在两个重复单元之间的SET结构域的中央模块相互作用而产生的。其中一个重复序列似乎已经获得了适应性，这有助于它专注于BMPMet结合，而第二个重复序列有助于组蛋白相互作用，并定位一个关键的活性位点残基。SET结构域的中央模块为活性位点提供了一个关键的天冬酰胺，其结构特征表明，它也可能是由包含核心桶的重复序列之一的进一步复制引起的。然而，由于缺乏专性二聚化配偶体，它似乎在结构上与两个典型重复序列不同。在祖先二聚体的两个重复的空间位置似乎有利于形成典型的SET域的结构结。在SPOUT结构域甲基转移酶中可以看到一个类似的结，这代表了两种不相关的甲基化酶中活性位点相关构型的收敛进化。因此，SET结构域提供了一种通过复制结构简单的非酶单位来创新复杂酶折叠的模型。
SET domains are protein lysine methyltransferases that methylate diverse proteins, such as, histones, Rubisco and cytochrome C. In particular, they play an important role in the dynamics of the eukaryotic chromatin and are present in several chromatin-associated proteins. Recently, structures of several SET domains have been solved, and they contain a conserved fold that is unrelated to previously characterized methyltransferases, which possess either Rossmann fold or SPOUT domains. Phylogenetic and phyletic-profile analysis of the SET domain suggests that it was an evolutionary "invention" of the eukaryotic lineage, with secondary lateral transfers to bacteria. We show that the conserved N- and C-terminal regions, which comprise the core barrel-like module of the SET domain, are symmetric repeats of a simple 3-stranded unit. Furthermore, the two symmetrically arranged repeats contribute to the binding sites for the two substrates of the SET domain. This suggests the SET domain arose from an ancestral dimer of this 3-stranded unit, with each unit probably functioning as generic-ligand binding structure. The divergence between the two repeat units appears to have arisen as a result of their interactions with the central module of the SET domain, which was inserted between the two repeats. One of the repeats appears to have acquired adaptations, which helped it to specialize in AdoMet binding, whereas the second repeat contributed to histone-interaction, and in orienting a crucial active site residue. The central module of the SET domain supplies a critical asparagine to the active site, and its structural features suggest that it may have also arisen from a further duplication of one of the repeats comprising the core barrel. However, it appears to have structurally diverged from the two canonical repeats due to the lack of an obligate dimerization partner. The spatial position of the two repeats in the ancestral dimer appears to have favored the formation of the structural knot typical of the SET domain. A comparable knot is seen in the SPOUT-domain methyltransferases, and this represents a case of convergent evolution of an active-site-associated configuration in two otherwise unrelated classes of methylases. Thus, the SET domain provides a model for the innovation of a complex enzymatic fold through the duplications of a structurally simple non-enzymatic unit.