Abstract
Mitochondrial RNA polymerase produces long polycistronic precursors that contain the mRNAs, rRNAs and tRNAs needed for mitochondrial translation. Mitochondrial RNase P (mt-RNase P) initiates the maturation of the precursors by cleaving at the 5′ ends of the tRNAs. Human mt-RNase P is only active as a tripartite complex (mitochondrial RNase P proteins 1–3; MRPP1-3), whereas plant and trypanosomal RNase Ps (PRORPs)—albeit homologous to MRPP3—are active as single proteins. The reason for this discrepancy has so far remained obscure. Here, we present the crystal structure of human MRPP3, which features a remarkably distorted and hence non-productive active site that we propose will switch to a fully productive state only upon association with MRPP1, MRPP2 and pre-tRNA substrate. We suggest a mechanism in which MRPP1 and MRPP2 both deliver the pre-tRNA substrate and activate MRPP3 through an induced-fit process.
Highlights
Transcription in human mitochondria gives rise to two long polycistronic transcripts that are subsequently processed into mature mRNAs, tRNAs and rRNAs by the mitochondrial RNA-processing machinery
The third subunit, MRPP3, contains the sequence features of a zinc-binding domain and an N-terminal, putative RNAbinding pentatricopeptide repeat (PPR) domain, where the PPR repeats are helix-turn-helix motifs of ∼35 amino acids and are found in a large number of RNA binding eukaryotic proteins [11]
Longer sequence replacements were created by In-Fusion HD cloning (Clontech), using gBlocks (IDT) for the longer replacements
Summary
Transcription in human mitochondria gives rise to two long polycistronic transcripts that are subsequently processed into mature mRNAs, tRNAs and rRNAs by the mitochondrial RNA-processing machinery. MRPP1 ( known as TRM10C: tRNA methyltransferase 10 homolog) and MRPP2 ( known as SDR5C1: short chain dehydrogenase/reductase family 5C member 1) form a strong protein complex [6] and perform the N1-methylation of adenosine and guanosine at position 9 (m1A9 and m1G9, respectively) of human mt-tRNAs [7,8,9]. This methylation is necessary for the proper folding of at least one mitochondrial tRNA [8]; a majority of human mitochondrial tRNAs contain an m1A9 or m1G9 [10].
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