Mutations of human mitochondrial transfer RNA (tRNA) are implicated in a variety of multisystemic diseases. The most prevalent pathogenic mitochondrial mutation is the A3243G substitution within the gene for tRNALeu(UUR). Here we describe the pronounced structural change promoted by this mutation. The A3243G mutation induces the formation of a tRNA dimer that strongly self-associates under physiological conditions. The dimerization interface in the mutant tRNA is a self-complementary hexanucleotide in the D-stem, a particularly weak structural element within tRNALeu(UUR). Aminoacylation of the A3243G mutant is significantly attenuated, and mutational studies indicate that dimerization is partially responsible for the observed loss of function. The disruption of a conserved tertiary structural contact also contributes to the functional defect. The pathogenic mutation is proposed to interfere with the cellular function of human mitochondrial tRNALeu(UUR) by destabilizing the native structure and facilitating the formation of a dimeric complex with low biological activity.
ASJC Scopus subject areas
- Structural Biology