8P8X
Crystal structure of a pathogenic mutant variant of human mitochodnrial PheRS
Summary for 8P8X
| Entry DOI | 10.2210/pdb8p8x/pdb |
| Descriptor | Phenylalanine--tRNA ligase, mitochondrial, PHENYLALANINE (3 entities in total) |
| Functional Keywords | phenylalanyl-trna synthetase, fars2, mitochondria, mitochondrial disease, class ii aminoacyl-trna ligase, alpha-beta domain, atp binding, amino acid binding, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 48579.09 |
| Authors | |
| Primary citation | Chen, W.,Rehsi, P.,Thompson, K.,Yeo, M.,Stals, K.,He, L.,Schimmel, P.,Chrzanowska-Lightowlers, Z.M.A.,Wakeling, E.,Taylor, R.W.,Kuhle, B. Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease. Mol.Genet.Metab., 140:107657-107657, 2023 Cited by PubMed Abstract: FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS), which is essential for charging mitochondrial (mt-) tRNA with phenylalanine for use in intramitochondrial translation. Many biallelic, pathogenic FARS2 variants have been described previously, which are mostly associated with two distinct clinical phenotypes; an early onset epileptic mitochondrial encephalomyopathy or a later onset spastic paraplegia. In this study, we report on a patient who presented at 3 weeks of age with tachypnoea and poor feeding, which progressed to severe metabolic decompensation with lactic acidosis and seizure activity followed by death at 9 weeks of age. Rapid trio whole exome sequencing identified compound heterozygous FARS2 variants including a pathogenic exon 2 deletion on one allele and a rare missense variant (c.593G > T, p.(Arg198Leu)) on the other allele, necessitating further work to aid variant classification. Assessment of patient fibroblasts demonstrated severely decreased steady-state levels of mtPheRS, but no obvious defect in any components of the oxidative phosphorylation system. To investigate the potential pathogenicity of the missense variant, we determined its high-resolution crystal structure, demonstrating a local structural destabilization in the catalytic domain. Moreover, the R198L mutation reduced the thermal stability and impaired the enzymatic activity of mtPheRS due to a lower binding affinity for tRNA and a slower turnover rate. Together these data confirm the pathogenicity of this FARS2 variant in causing early-onset mitochondrial epilepsy. PubMed: 37523899DOI: 10.1016/j.ymgme.2023.107657 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.46 Å) |
Structure validation
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