Tristetraprolin (TTP), the prototype member of the protein family of the same name, was originally discovered as the product of a rapidly inducible gene in mouse cells. Development of a knockout (KO) mouse established that absence of the protein led to a severe inflammatory syndrome, due in part to elevated levels of tumor necrosis factor (TNF). TTP was found to bind directly and with high affinity to specific AU-rich sequences in the 3'-untranslated region of the TNF mRNA. This initial binding led to promotion of TNF mRNA decay and inhibition of its translation. Many additional TTP target mRNAs have since been identified, some of which are cytokines and chemokines involved in the inflammatory response. There are three other proteins in the mouse with similar activities and domain structures, but whose KO phenotypes are remarkably different. Moreover, proteins with similar domain structures and activities have been found throughout eukaryotes, demonstrating that this protein family arose from an ancient ancestor. The defining characteristic of this protein family is the tandem zinc finger (TZF) domain, a 64 amino acid sequence with many conserved residues that is responsible for the direct RNA binding. We discuss here many aspects of this protein domain that have been elucidated since the original discovery of TTP, including its sequence conservation throughout eukarya; its apparent continued evolution in some lineages; its functional dependence on many key conserved residues; its "interchangeability" among evolutionarily distant species; and the evidence that RNA binding is required for the physiological functions of the proteins. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

中文翻译：

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Tristetraprolin蛋白家族成员的串联锌指RNA结合结构域。

Tristetraprolin（TTP），同名蛋白质家族的原型成员，最初被发现是小鼠细胞中快速诱导基因的产物。敲除（KO）小鼠的发展证实，该蛋白的缺失会导致严重的炎症综合症，部分原因是肿瘤坏死因子（TNF）水平升高。发现TTP与TNF mRNA的3'-非翻译区中的特定富含AU的序列直接结合并具有高亲和力。这种初始结合导致TNF mRNA衰变的促进和其翻译的抑制。此后已鉴定出许多其他的TTP靶mRNA，其中一些是参与炎症反应的细胞因子和趋化因子。小鼠中还有其他三种具有相似活性和域结构的蛋白质，但其KO表型明显不同。此外，在整个真核生物中都发现了具有相似结构域结构和活性的蛋白质，这表明该蛋白质家族起源于古代祖先。该蛋白质家族的定义特征是串联锌指（TZF）域，这是一个64个氨基酸的序列，带有许多保守的残基，直接与RNA结合。我们在这里讨论了自最初发现TTP以来已阐明的该蛋白质结构域的许多方面，包括整个真核生物中的序列保守性；在某些血统中其明显的持续发展；其功能依赖于许多关键的保守残基；在进化距离遥远的物种之间的“互换性”；RNA结合是蛋白质生理功能所必需的证据。本文归类为：