ArticleProceedings of the National Academy of Sciences of the United States of America2016
Two crystal structures reveal design for repurposing the C-Ala domain of human AlaRS.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 28 citations in OpenAlex.
- Advances in Research onGenes · 2026Review
- Emerging roles of lysine lactyltransferases and lactylation.Nature cell biology · 2025Review
- Eukaryotic AlaX provides multiple checkpoints for quality and quantity of aminoacyl-tRNAs in translation.Nucleic acids research · 2024Article
- A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations.Human molecular genetics · 2023Article
- An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia.Translational neurodegeneration · 2023Article
- A naturally occurring mini-alanyl-tRNA synthetase.Communications biology · 2023Article
- Dominant aminoacyl-tRNA synthetase disorders: lessons learned fromFrontiers in neuroscience · 2023Review
- Editorial: Noncanonical functions of Aminoacyl-tRNA synthetases.Frontiers in physiology · 2023Article
- Gain of C-Ala enables AlaRS to target the L-shaped tRNAAla.Nucleic acids research · 2022Article
- The uniqueness of AlaRS and its human disease connections.RNA biology · 2021Review
- Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: A gain or a loss?Journal of neurochemistry · 2021Review
- CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Chimeric design of pyrrolysyl-tRNA synthetase/tRNA pairs and canonical synthetase/tRNA pairs for genetic code expansion.Nature communications · 2020Article
- Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy.Nature communications · 2019Article
- Neurodegenerative Charcot-Marie-Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases.The Journal of biological chemistry · 2019Review
- Distinct ways of G:U recognition by conserved tRNA binding motifs.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease.Human molecular genetics · 2017Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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