Abstract
Human mitochondrial transcripts contain messenger and ribosomal RNAs flanked by transfer RNAs (tRNAs), which are excised by mitochondrial RNase (mtRNase) P and Z to liberate all RNA species. In contrast to nuclear or bacterial RNase P, mtRNase P is not a ribozyme but comprises three protein subunits that carry out RNA cleavage and methylation by unknown mechanisms. Here, we present the cryo-EM structure of human mtRNase P bound to precursor tRNA, which reveals a unique mechanism of substrate recognition and processing. Subunits TRMT10C and SDR5C1 form a subcomplex that binds conserved mitochondrial tRNA elements, including the anticodon loop, and positions the tRNA for methylation. The endonuclease PRORP is recruited and activated through interactions with its PPR and nuclease domains to ensure precise pre-tRNA cleavage. The structure provides the molecular basis for the first step of RNA processing in human mitochondria.
Highlights
Human mitochondrial transcripts contain messenger and ribosomal RNAs flanked by transfer RNAs, which are excised by mitochondrial RNase P and Z to liberate all RNA species
MtDNA is transcribed by a mitochondrial RNA polymerase, which produces polycistronic primary transcripts that contain ribosomal RNAs and messenger RNAs interspersed by transfer RNAs2–4
We present the structure of human mitochondrial RNase (mtRNase) P, which carries out the initial steps of mitochondrial RNA processing to produce individual RNA species from primary transcripts
Summary
Human mitochondrial transcripts contain messenger and ribosomal RNAs flanked by transfer RNAs (tRNAs), which are excised by mitochondrial RNase (mtRNase) P and Z to liberate all RNA species. Mammalian mitochondrial RNase P is evolutionarily unique because it is a multisubunit protein complex consisting of PRORP ( known as MRPP3), which is homologous to single-subunit PRORPs, and the two additional subunits TRMT10C ( known as MRPP1) and SDR5C1 ( known as MRPP2)[7,15] This multimeric complex carries out both pre-tRNA cleavage and methylation, and is a central player in mitochondrial gene expression. The molecular basis for its dual function and the reasons for the emergence of this unique machinery are not known It is not clear how mtRNase P recognizes its substrate, as conserved elements recognized by RNA-based RNase P enzymes and plant PRORP1 are variable or absent in mammalian mitochondrial tRNAs25–28. In vitro data suggest that the TRMT10C–SDR5C1 subcomplex may act as a processing platform to facilitate sequential RNA processing steps[29], but the molecular basis for this is unknown
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