期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：50
页码：14300-14305
DOI：10.1073/pnas.1617316113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceHere we present an exception that supports the rule that the 20 human tRNA synthetases acquired new architectures to expand their functions during evolution. The new features are associated with novel, appended domains that are absent in prokaryotes and retained by their many splice variants. Alanyl-tRNA synthetase (AlaRS) is the single example that has a prototypical appended domain--C-Ala--even in prokaryotes, which is spliced out in humans. X-ray structural, small-angle X-ray scattering, and functional analysis showed that human C-Ala lost its prokaryotic tRNA functional role and instead was reshaped into a nuclear DNA-binding protein. Thus, we report another paradigm for tRNA synthetase acquisition of a novel function, namely, repurposing a preexisting domain rather than addition of a new one. The 20 aminoacyl tRNA synthetases (aaRSs) couple each amino acid to their cognate tRNAs. During evolution, 19 aaRSs expanded by acquiring novel noncatalytic appended domains, which are absent from bacteria and many lower eukaryotes but confer extracellular and nuclear functions in higher organisms. AlaRS is the single exception, with an appended C-terminal domain (C-Ala) that is conserved from prokaryotes to humans but with a wide sequence divergence. In human cells, C-Ala is also a splice variant of AlaRS. Crystal structures of two forms of human C-Ala, and small-angle X-ray scattering of AlaRS, showed that the large sequence divergence of human C-Ala reshaped C-Ala in a way that changed the global architecture of AlaRS. This reshaping removes the role of C-Ala in prokaryotes for docking tRNA and instead repurposes it to form a dimer interface presenting a DNA-binding groove. This groove cannot form with the bacterial ortholog. Direct DNA binding by human C-Ala, but not by bacterial C-Ala, was demonstrated. Thus, instead of acquiring a novel appended domain like other human aaRSs, which engendered novel functions, a new AlaRS architecture was created by diversifying a preexisting appended domain.
