Liu Jianming, Yang Xiang-Lei, Ewalt Karla L, Schimmel Paul
The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC-379, La Jolla, California 92037, USA.
Biochemistry. 2002 Dec 3;41(48):14232-7. doi: 10.1021/bi0205395.
Aminoacyl-tRNA synthetases catalyze the attachment of amino acids to their cognate tRNAs. A link was recently established between protein biosynthesis and cytokine signal transduction. Human tyrosyl-tRNA synthetase can be split into two fragments, each of which has a distinct cytokine function. This activity is specific to the human enzyme. It is absent in the enzymes from lower organisms such as bacteria and yeast. Here, yeast tyrosyl-tRNA synthetase (TyrRS), which lacks cytokine activity, was used as a model to explore how a human tyrosyl-tRNA synthetase during evolution acquired novel functions beyond aminoacylation. We found that a rationally designed mutant yeast TyrRS(ELR) gained cytokine function. The mutant yeast enzyme gained this function without sacrifice of aminoacylation activity. Therefore, relatively simple alteration of a basic structural motif imparts cytokine activity to a tRNA synthetase while preserving its canonical function. Further work established that mutational switching of a yeast protein to a mammalian-like cytokine was specific to this synthetase and not to just any yeast ortholog of a mammalian cytokine.
氨酰 - tRNA合成酶催化氨基酸与其对应的tRNA连接。最近在蛋白质生物合成与细胞因子信号转导之间建立了联系。人酪氨酰 - tRNA合成酶可分为两个片段，每个片段都具有独特的细胞因子功能。这种活性是人类酶所特有的。在细菌和酵母等低等生物的酶中不存在。在此，缺乏细胞因子活性的酵母酪氨酰 - tRNA合成酶（TyrRS）被用作模型，以探索人类酪氨酰 - tRNA合成酶在进化过程中如何获得除氨酰化之外的新功能。我们发现，经过合理设计的突变型酵母TyrRS（ELR）获得了细胞因子功能。突变型酵母酶在不牺牲氨酰化活性的情况下获得了这种功能。因此，对基本结构基序进行相对简单的改变就能赋予tRNA合成酶细胞因子活性，同时保留其经典功能。进一步的研究表明，将酵母蛋白突变转变为类似哺乳动物的细胞因子，这种转变是该合成酶所特有的，而不仅仅是任何酵母中哺乳动物细胞因子的直系同源物所具有的特性。
