Human tRNA synthetase catalytic nulls with diverse functions

作者：Wing‐Sze Lo, Elisabeth Gardiner, Zhiwen Xu, Ching-Fun Lau, Feng Wang, Jie Zhou, John Mendlein, Leslie A. Nangle, Kyle P. Chiang, Xiang‐Lei Yang, K. Au, Wing Hung Wong, Min Guo, Mingjie Zhang, Paul Schimmel · 发表于：Science · 年份：2014 · DOI：10.1126/science.1252943 · 被引用次数：126 · 研究领域：RNA and protein synthesis mechanisms、RNA modifications and cancer、RNA Research and Splicing

Genetic efficiency in higher organisms depends on mechanisms to create multiple functions from single genes. To investigate this question for an enzyme family, we chose aminoacyl tRNA synthetases (AARSs). They are exceptional in their progressive and accretive proliferation of noncatalytic domains as the Tree of Life is ascended. Here we report discovery of a large number of natural catalytic nulls (CNs) for each human AARS. Splicing events retain noncatalytic domains while ablating the catalytic domain to create CNs with diverse functions. Each synthetase is converted into several new signaling proteins with biological activities "orthogonal" to that of the catalytic parent. We suggest that splice variants with nonenzymatic functions may be more general, as evidenced by recent findings of other catalytically inactive splice-variant enzymes.