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Valyl-tRNA Synthetase

Valyl-tRNA synthetase (ValRS, also known as valine tRNA ligase) is the enzyme responsible for charging tRNA(val) with valine. In humans, ValRS exists in a cytosolic and a mitochondrial form. The cytosolic form is a monomeric 140kDa protein encoded by VARS1 while the mitochondrial form is a slightly smaller monomeric 118kDa protein encoded by VARS2. ValRS is a member of the class-Ia subfamily of aminoacyl-tRNA synthetases, defined by a characteristic α helix bundle at the C-terminus used for tRNA recognition. Aminoacyl-tRNA synthetases are generally highly conserved, and ValRS exhibits high structural similarity to IleRS and LeuRS. Human disease related to mutations in ValRS are very rare but life-threatening. Biallelic mutations in ValRS are associated with neurological defects and global developmental delay, including epileptic encephalopathy, microcephaly and microphthalmia^[1]. These phenotypes are thought to be due to a global lack of charged tRNA molecules which induces an amino acid starvation response and inhibits cell proliferation^[2].

spinqualitylabelsall models Caption for this structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Structural Overview The major structural elements of ValRS, like other class-Ia aminoacyl-tRNA synthetases, are a helical insertion into the N-terminal half of a Rossmann fold domain and an α-helix bundle domain near the C-terminus[3]. Additionally, ValRS has a large editing domain important in the discrimination between valine and structurally similar amino acids. A positively charged (SC-fold) domain contacts C11 and C25 of the D-loop of tRNA(val), creating a space between the anticodon recognition and editing domains where the tRNA is "pinched" and held onto.

References

1. ↑ doi: https://dx.doi.org/doi.org/10.1038/s41467-018-07067-3
2. ↑ doi: https://dx.doi.org/doi.org/10.3389/fcell.2019.00067
3. ↑ doi: https://dx.doi.org/10.1261/rna.2760703