5mgh
Crystal structure of pathogenic mutants of human mitochodnrial PheRS
Structural highlights
FunctionSYFM_HUMAN Catalyzes direct attachment of p-Tyr (Tyr) to tRNAPhe. Permits also, with a lower efficiency, the attachment of m-Tyr to tRNAPhe, thereby opening the way for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into proteins.[1] Publication Abstract from PubMedMutations in the mitochondrial aminoacyl-tRNA synthetases (mtaaRSs) can cause profound clinical presentations, and have manifested as diseases with very selective tissue specificity. To date most of the mtaaRS mutations could be phenotypically recognized, such that clinicians could identify the affected mtaaRS from the symptoms alone. Among the recently reported pathogenic variants are point mutations in FARS2 gene, encoding the human mitochondrial PheRS. Patient symptoms range from spastic paraplegia to fatal infantile Alpers encephalopathy. How clinical manifestations of these mutations relate to the changes in three-dimensional structures and kinetic characteristics remains unclear, although impaired aminoacylation has been proposed as possible etiology of diseases. Here, we report four crystal structures of HsmtPheRS mutants, and extensive MD simulations for wild-type and nine mutants to reveal the structural changes on dynamic trajectories of HsmtPheRS. Using steady-state kinetic measurements of phenylalanine activation and tRNAPhe aminoacylation, we gained insight into the structural and kinetic effects of mitochondrial disease-related mutations in FARS2 gene. Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2.,Kartvelishvili E, Tworowski D, Vernon H, Moor N, Wang J, Wong LJ, Chrzanowska-Lightowlers Z, Safro M Protein Sci. 2017 Apr 17. doi: 10.1002/pro.3176. PMID:28419689[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
