Structures of the human mitochondrial ribosome recycling complexes reveal distinct mechanisms of recycling and antibiotic resistance

Abstract Ribosomes are recycled for a new round of translation initiation by dissociation of ribosomal subunits, messenger RNA and transfer RNA from their translational post-termination complex. Mitochondrial ribosome recycling factor (RRFmt) and a recycling-specific homolog of elongation factor G (...

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Bibliographic Details
Published inbioRxiv
Main Authors Koripella, Ravi Kiran, Deep, Ayush, Agrawal, Ekansh K, Keshavan, Pooja, Banavali, Nilesh K, Agrawal, Rajendra K
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 21.12.2020
Subjects
Antibiotic resistance
Antibiotics
Drug resistance
Elongation
Fusidic acid
Isoforms
Mitochondria
mRNA
Recycling
Ribosomal subunits
Ribosomes
rRNA
Transfer RNA
Translation initiation
Translation termination
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Summary:Abstract Ribosomes are recycled for a new round of translation initiation by dissociation of ribosomal subunits, messenger RNA and transfer RNA from their translational post-termination complex. Mitochondrial ribosome recycling factor (RRFmt) and a recycling-specific homolog of elongation factor G (EF-G2mt) are two proteins with mitochondria-specific additional sequences that catalyze the recycling step in human mitochondria. We have determined high-resolution cryo-EM structures of the human 55S mitochondrial ribosome (mitoribosome) in complex with RRFmt, and the mitoribosomal large 39S subunit in complex with both RRFmt and EF-G2mt. In addition, we have captured the structure of a short-lived intermediate state of the 55S•RRFmt•EF-G2mt complex. These structures clarify the role of a mitochondria-specific segment of RRFmt in mitoribosome recycling, identify the structural distinctions between the two isoforms of EF-Gmt that confer their functional specificity, capture recycling-specific conformational changes in the L7/L12 stalk-base region, and suggest a distinct mechanistic sequence of events in mitoribosome recycling. Furthermore, biochemical and structural assessments of the sensitivity of EF-G2mt to the antibiotic fusidic acid reveals that the molecular mechanism of antibiotic resistance for EF-G2mt is markedly different from that exhibited by mitochondrial elongation factor EF-G1mt, suggesting that these two homologous mitochondrial proteins have evolved diversely to negate the effect of a bacterial antibiotics. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.12.20.423689