User:Harry Gritsch/Sandbox 1
From Proteopedia
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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<ref>DOI doi.org/10.1038/s41467-018-07067-3</ref>. 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<ref>DOI doi.org/10.3389/fcell.2019.00067</ref>. | 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<ref>DOI doi.org/10.1038/s41467-018-07067-3</ref>. 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<ref>DOI doi.org/10.3389/fcell.2019.00067</ref>. | ||
| - | <StructureSection load=' | + | <StructureSection load='1ivs' size='340' side='right' caption='Caption for this structure' scene=''> |
== Structural Overview == | == 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<ref>DOI 10.1261/rna.2760703</ref>. Additionally, ValRS has a large editing domain important in the discrimination between valine and structurally similar amino acids. A positively charged <scene name='10/1078173/Sc-fold_domain/3'>stem-contact-fold</scene> (SC-fold) domain contacts the D-loop of tRNA(val), creating a space between the anticodon recognition and editing domains where the tRNA is "pinched" and held onto. This positive patch lines up with the negative backbone of the D-stem, with the Arg570 side chain contacting the oxygens of C11 and C25, the aromatic nitrogen of Trp571 forming weak bonds with the oxygens of U12, and the side chain of Arg566 hydrogen bonding with the backbone of C13. | 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<ref>DOI 10.1261/rna.2760703</ref>. Additionally, ValRS has a large editing domain important in the discrimination between valine and structurally similar amino acids. A positively charged <scene name='10/1078173/Sc-fold_domain/3'>stem-contact-fold</scene> (SC-fold) domain contacts the D-loop of tRNA(val), creating a space between the anticodon recognition and editing domains where the tRNA is "pinched" and held onto. This positive patch lines up with the negative backbone of the D-stem, with the Arg570 side chain contacting the oxygens of C11 and C25, the aromatic nitrogen of Trp571 forming weak bonds with the oxygens of U12, and the side chain of Arg566 hydrogen bonding with the backbone of C13. | ||
Revision as of 13:41, 21 April 2025
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].
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