Unique features of mammalian mitochondrial translation initiation revealed by cryo-EM

Eva Kummer, Marc Leibundgut, Oliver Rackham, Richard G. Lee, Daniel Boehringer, Aleksandra Filipovska and Nenad Ban ()
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Eva Kummer: Institute of Molecular Biology and Biophysics, ETH Zurich
Marc Leibundgut: Institute of Molecular Biology and Biophysics, ETH Zurich
Oliver Rackham: Centre for Medical Research, QEII Medical Centre and School of Molecular Sciences, The University of Western Australia
Richard G. Lee: Centre for Medical Research, QEII Medical Centre and School of Molecular Sciences, The University of Western Australia
Daniel Boehringer: Institute of Molecular Biology and Biophysics, ETH Zurich
Aleksandra Filipovska: Centre for Medical Research, QEII Medical Centre and School of Molecular Sciences, The University of Western Australia
Nenad Ban: Institute of Molecular Biology and Biophysics, ETH Zurich

Nature, 2018, vol. 560, issue 7717, 263-267

Abstract: Abstract Mitochondria maintain their own specialized protein synthesis machinery, which in mammals is used exclusively for the synthesis of the membrane proteins responsible for oxidative phosphorylation1,2. The initiation of protein synthesis in mitochondria differs substantially from bacterial or cytosolic translation systems. Mitochondrial translation initiation lacks initiation factor 1, which is essential in all other translation systems from bacteria to mammals3,4. Furthermore, only one type of methionyl transfer RNA (tRNAMet) is used for both initiation and elongation4,5, necessitating that the initiation factor specifically recognizes the formylated version of tRNAMet (fMet–tRNAMet). Lastly, most mitochondrial mRNAs do not possess 5′ leader sequences to promote mRNA binding to the ribosome2. There is currently little mechanistic insight into mammalian mitochondrial translation initiation, and it is not clear how mRNA engagement, initiator-tRNA recruitment and start-codon selection occur. Here we determine the cryo-EM structure of the complete translation initiation complex from mammalian mitochondria at 3.2 Å. We describe the function of an additional domain insertion that is present in the mammalian mitochondrial initiation factor 2 (mtIF2). By closing the decoding centre, this insertion stabilizes the binding of leaderless mRNAs and induces conformational changes in the rRNA nucleotides involved in decoding. We identify unique features of mtIF2 that are required for specific recognition of fMet–tRNAMet and regulation of its GTPase activity. Finally, we observe that the ribosomal tunnel in the initiating ribosome is blocked by insertion of the N-terminal portion of mitochondrial protein mL45, which becomes exposed as the ribosome switches to elongation mode and may have an additional role in targeting of mitochondrial ribosomes to the protein-conducting pore in the inner mitochondrial membrane.

Date: 2018
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DOI: 10.1038/s41586-018-0373-y

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