Blackshear Perry J, Perera Lalith
1 Laboratories of Signal Transduction, National Institute of Environmental Health Sciences , Research Triangle Park, North Carolina.
J Interferon Cytokine Res. 2014 Apr;34(4):297-306. doi: 10.1089/jir.2013.0150.
In humans, the tristetraprolin or TTP family of CCCH tandem zinc finger (TZF) proteins comprises 3 members, encoded by the genes ZFP36, ZFP36L1, and ZFP36L2. These proteins have direct orthologues in essentially all vertebrates studied, with the exception of birds, which appear to lack a version of ZFP36. Additional family members are found in rodents, amphibians, and fish. In general, the encoded proteins contain 2 critical macromolecular interaction domains: the CCCH TZF domain, which is necessary for high-affinity binding to AU-rich elements in mRNA; and an extreme C-terminal domain that, in the case of TTP, interacts with NOT1, the scaffold of a large multi-protein complex that contains deadenylases. TTP and its related proteins act by first binding to AU-rich elements in mRNA, and then recruiting deadenylases to the mRNA, where they can processively remove the adenosine residues from the poly(A) tail. Highly conserved TZF domains have been found in unicellular eukaryotes such as yeasts, and these domains can bind AU-rich elements that resemble those bound by the mammalian proteins. However, certain fungi appear to lack proteins with intact TZF domains, and the TTP family proteins that are expressed in other fungi often lack the characteristic C-terminal NOT1 binding domain found in the mammalian proteins. For these reasons, we investigated the phylogenetic distribution of the relevant sequences in available databases. Both domains are present in family member proteins from most lineages of eukaryotes, suggesting their mutual presence in a common ancestor. However, the vertebrate type of NOT1-binding domain is missing in most fungi, and the TZF domain itself has disappeared or degenerated in recently evolved fungi. Nonetheless, both domains are present together in the proteins from several unicellular eukaryotes, including at least 1 fungus, and they seem to have remained together during the evolution of metazoans.
在人类中，CCCH串联锌指（TZF）蛋白的三磷酸腺苷结合盒转运体家族包含3个成员，由ZFP36、ZFP36L1和ZFP36L2基因编码。除鸟类外，在基本上所有已研究的脊椎动物中都有这些蛋白的直系同源物，鸟类似乎缺乏ZFP36的对应物。在啮齿动物、两栖动物和鱼类中还发现了其他家族成员。一般来说，编码的蛋白质包含2个关键的大分子相互作用结构域：CCCH TZF结构域，它是与mRNA中富含AU的元件高亲和力结合所必需的；以及一个极端的C末端结构域，就三磷酸腺苷结合盒转运体而言，它与NOT1相互作用，NOT1是一个包含去腺苷酸化酶的大型多蛋白复合物的支架。三磷酸腺苷结合盒转运体及其相关蛋白的作用方式是，首先与mRNA中富含AU的元件结合，然后将去腺苷酸化酶招募到mRNA上，在那里它们可以从多聚腺苷酸尾巴上逐步去除腺苷残基。在单细胞真核生物如酵母中发现了高度保守的TZF结构域，这些结构域可以结合类似于哺乳动物蛋白所结合的富含AU的元件。然而，某些真菌似乎缺乏具有完整TZF结构域的蛋白质，而在其他真菌中表达的三磷酸腺苷结合盒转运体家族蛋白通常缺乏哺乳动物蛋白中发现的特征性C末端NOT1结合结构域。出于这些原因，我们研究了可用数据库中相关序列的系统发育分布。这两个结构域存在于大多数真核生物谱系的家族成员蛋白中，表明它们在共同祖先中共同存在。然而，大多数真菌中缺少脊椎动物类型的NOT1结合结构域，并且TZF结构域本身在最近进化的真菌中已经消失或退化。尽管如此，这两个结构域在几种单细胞真核生物的蛋白质中共同存在，包括至少1种真菌，并且它们似乎在后生动物的进化过程中一直共同存在。
