ABSTRACT

Among the 20 cytoplasmic aminoacyl-tRNA synthetases (aaRSs), alanyl-tRNA synthetase (AlaRS) has unique features. AlaRS is the only aaRS that exclusively recognizes a single G3:U70 wobble base pair in the acceptor stem of tRNA, which serves as the identity element for both the synthetic and the proofreading activities of the synthetase. The recognition is relaxed during evolution and eukaryotic AlaRS can mis-aminoacylate noncognate tRNAs with a G4:U69 base pair seemingly as a deliberate gain of function for unknown reasons. Unlike other class II aaRSs, dimerization of AlaRS is not necessarily required for aminoacylation possibly due to functional compensations from the C-terminal domain (C-Ala). In contrast to other 19 cytoplasmic aaRSs that append additional domains or motifs to acquire new functions during evolution, the functional expansion of AlaRS is likely achieved through transformations of the existing C-Ala. Given both essential canonical and diverse non-canonical roles of AlaRS, dysfunction of AlaRS leads to neurodegenerative disorders in human and various pathological phenotypes in mouse models. In this review, the uniqueness of AlaRS in both physiological and pathological events is systematically discussed, with a particular focus on its novel functions gained in evolution.

摘要

在 20 种细胞质氨酰-tRNA 合成酶 (aaRS) 中，丙氨酰-tRNA 合成酶 (AlaRS) 具有独特的特点。AlaRS 是唯一一个专门识别 tRNA 受体茎中的单个 G3:U70 摆动碱基对的 aaRS，它作为合成酶的合成和校对活动的标识元素。在进化过程中识别是放松的，真核生物 AlaRS 可以错误地氨酰化具有 G4:U69 碱基对的非同源 tRNA，这似乎是出于未知原因故意获得的功能。与其他 II 类 aaRS 不同，氨酰化不一定需要 AlaRS 的二聚化，这可能是由于来自 C 末端结构域 (C-Ala) 的功能补偿。与其他 19 种细胞质 aaRS 相比，这些 aaRS 在进化过程中附加了额外的结构域或基序以获取新功能，AlaRS 的功能扩展很可能是通过对现有 C-Ala 的改造来实现的。鉴于 AlaRS 的基本规范和不同的非规范作用，AlaRS 的功能障碍导致人类神经退行性疾病和小鼠模型中的各种病理表型。在这篇综述中，系统地讨论了 AlaRS 在生理和病理事件中的独特性，特别关注其在进化中获得的新功能。