Abstract
Mitochondrial ribosomes are specialized for the synthesis of membrane proteins responsible for oxidative phosphorylation. Mammalian mitoribosomes have diverged considerably from the ancestral bacterial ribosomes and feature dramatically reduced ribosomal RNAs. The structural basis of the mammalian mitochondrial ribosome assembly is currently not well understood. Here we present eight distinct assembly intermediates of the human large mitoribosomal subunit involving seven assembly factors. We discover that the NSUN4-MTERF4 dimer plays a critical role in the process by stabilizing the 16S rRNA in a conformation that exposes the functionally important regions of rRNA for modification by the MRM2 methyltransferase and quality control interactions with the conserved mitochondrial GTPase MTG2 that contacts the sarcin-ricin loop and the immature active site. The successive action of these factors leads to the formation of the peptidyl transferase active site of the mitoribosome and the folding of the surrounding rRNA regions responsible for interactions with tRNAs and the small ribosomal subunit.
Highlights
Mitochondrial ribosomes are specialized for the synthesis of membrane proteins responsible for oxidative phosphorylation
To purify assembly intermediates of the human mitoribosomal large subunit (mt-LSU), we transfected human embryonic kidney cells with a tagged mitochondrial GTPase 1 (MTG1) (Supplementary Fig. 1), which is a homolog of bacterial RbgA18,19 and is essential for the production of functional mitoribosomes due to its involvement in the late stages of mt-LSU assembly prior to monosome formation[20,21]
States A0 and D, resemble the structures of the assembly intermediates described previously, where a MALSU1–L0R8F8–mt-ACP module is bound at the intersubunit face, whereas the ribosomal RNA (rRNA) is either disordered or in a nearly mature state, respectively[17]
Summary
Mitochondrial ribosomes are specialized for the synthesis of membrane proteins responsible for oxidative phosphorylation. We determined structures of eight distinct states of the human mt-LSU where a total of seven assembly factors (MTERF4, NSUN4, MRM2, MTG2, MALSU1, L0R8F8, and mt-ACP) were bound in different combinations.
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