Disease-associated mutations in mitochondrial precursor tRNAs affect binding, m1R9 methylation, and tRNA processing by mtRNase P
| Autor: | Markos Koutmos, Catherine A. Wilhelm, Agnes Karasik, Carol A. Fierke |
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| Rok vydání: | 2020 |
| Předmět: |
RNA Folding
Mitochondrial Diseases RNA Mitochondrial RNase P Mitochondrial disease TRNA processing Mitochondrion Biology Methylation 03 medical and health sciences RNA Transfer RNA Precursors medicine Protein biosynthesis Humans RNA Processing Post-Transcriptional Base Pairing Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences Base Sequence 030302 biochemistry & molecular biology Methyltransferases medicine.disease Molecular biology Mitochondria Enzyme chemistry Mutation Transfer RNA |
| Zdroj: | RNA. 27:420-432 |
| ISSN: | 1469-9001 1355-8382 |
| DOI: | 10.1261/rna.077198.120 |
| Popis: | Mitochondrial diseases linked to mutations in mitochondrial (mt) tRNA sequences are common. However, the contributions of these tRNA mutations to the development of diseases is mostly unknown. Mutations may affect interactions with (mt)tRNA maturation enzymes or protein synthesis machinery leading to mitochondrial dysfunction. In human mitochondria, in most cases the first step of tRNA processing is the removal of the 5′ leader of precursor tRNAs (pre-tRNA) catalyzed by the three-component enzyme, mtRNase P. Additionally, one component of mtRNase P, mitochondrial RNase P protein 1 (MRPP1), catalyzes methylation of the R9 base in pre-tRNAs. Despite the central role of 5′ end processing in mitochondrial tRNA maturation, the link between mtRNase P and diseases is mostly unexplored. Here, we investigate how 11 different human disease-linked mutations in (mt)pre-tRNAIle, (mt)pre-tRNALeu(UUR), and (mt)pre-tRNAMet affect the activities of mtRNase P. We find that several mutations weaken the pre-tRNA binding affinity (KDs are approximately two- to sixfold higher than that of wild-type), while the majority of mutations decrease 5′ end processing and methylation activity catalyzed by mtRNase P (up to ∼55% and 90% reduction, respectively). Furthermore, all of the investigated mutations in (mt)pre-tRNALeu(UUR) alter the tRNA fold which contributes to the partial loss of function of mtRNase P. Overall, these results reveal an etiological link between early steps of (mt)tRNA-substrate processing and mitochondrial disease. |
| Databáze: | OpenAIRE |
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