Unique domain appended to vertebrate tRNA synthetase is essential for vascular development

Abstract

New domains were progressively added to cytoplasmic aminoacyl transfer RNA (tRNA) synthetases during evolution. One example is the UNE-S domain, appended to seryl-tRNA synthetase (SerRS) in species that developed closed circulatory systems. Here we show using solution and crystal structure analyses and in vitro and in vivo functional studies that UNE-S harbours a robust nuclear localization signal (NLS) directing SerRS to the nucleus where it attenuates vascular endothelial growth factor A expression. We also show that SerRS mutants previously linked to vasculature abnormalities either deleted the NLS or have the NLS sequestered in an alternative conformation. A structure-based second-site mutation, designed to release the sequestered NLS, restored normal vasculature. Thus, the essential function of SerRS in vascular development depends on UNE-S. These results are the first to show an essential role for a tRNA synthetase-associated appended domain at the organism level, and suggest that acquisition of UNE-S has a role in the establishment of the closed circulatory systems of vertebrates.

Seryl-tRNA Synthetases in Translation and Beyond

“…In the last few years the crystal structure of archaeal Pyrococcus horikoshii SerRS [31] (homologous to conventional, bacterial-type enzyme) has been solved, eukaryotic SerRS from fungus Candida albicans [32] and protozoa Trypanosoma brucei [33] have their structures deciphered and finally the structure of human SerRS was determined. [34] Nowadays, the complete repertoire of SerRS crystal structures is available, from all three domains of life, including lower and higher eukaryotes and different cellular compartments. The archaeal and eukaryotic SerRSs in general recapitulate the structure and characteristics of the bacterial enzymes except in the case of SerRSs from methanogenic archaea.…”

“…Subsequent work on human SerRS revealed that UNE-S harbors a strong nuclear localization signal (NLS) directing SerRS to the nucleus where SerRS decreases VEGFA expression, [34] by antagonizing c-Myc, the major transcription factor promoting VEGFA expression. [43] In conclusion, vertebrate SerRS acts as a regulator of gene expression and the noncanonical role of SerRS essential for vascular development depends on UNE-S.…”

“…as this enzyme, in all domains of life, naturally lacks a domain specialized in editing. [21,28,34,53,54] In spite of that, it may hydrolyze both non-cognate and non-natural aminoacylAMPs, apparently within the synthetic module. [48,55] Work on the yeast SerRS provided the first strong indication that the pre-transfer editing reactions do not depend on the separate editing module.…”

tRN-A-RS Acts As Biomarker for Cancer and Other Diseases

“…In contrast, EPRS imposes translational silencing of VEGF-A via IFN-γ, thus acting as anti-angiogenic factor [112,113]. Impairment of vascular development may not only be related to cancer but to several cardiovascular diseases [114]. Finding the link of KARS to metastasis, one major cause of death in cancer, remains a challenge.…”

“…67LR on the other hand interacts with cell migrating component MAPK, and leads to metastatic transformation of cancer cell. Thus, KARS can form an anti-metastatic target [114]. The C-terminal domains of YARS and KARS act as inflammatory cytokines, which cause chronic inflammations in many cancers, particularly solid tumors.…”