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Structural basis of mitochondrial translation
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).ORCID-id: 0000-0003-2221-482X
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.ORCID-id: 0000-0003-4656-3362
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.ORCID-id: 0000-0002-5302-1740
Rekke forfattare: 42020 (engelsk)Inngår i: eLIFE, E-ISSN 2050-084X, Vol. 9, artikkel-id e58362Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Translation of mitochondrial messenger RNA (mt-mRNA) is performed by distinct mitoribosomes comprising at least 36 mitochondria-specific proteins. How these mitoribosomal proteins assist in the binding of mt-mRNA and to what extent they are involved in the translocation of transfer RNA (mt-tRNA) is unclear. To visualize the process of translation in human mitochondria, we report similar to 3.0 angstrom resolution structure of the human mitoribosome, including the L7/L12 stalk, and eight structures of its functional complexes with mt-mRNA, mt-tRNAs, recycling factor and additional trans factors. The study reveals a transacting protein module LRPPRC-SLIRP that delivers mt-mRNA to the mitoribosomal small subunit through a dedicated platform formed by the mitochondria-specific protein mS39. Mitoribosomal proteins of the large subunit mL40, mL48, and mL64 coordinate translocation of mt-tRNA. The comparison between those structures shows dynamic interactions between the mitoribosome and its ligands, suggesting a sequential mechanism of conformational changes.

sted, utgiver, år, opplag, sider
2020. Vol. 9, artikkel-id e58362
HSV kategori
Identifikatorer
URN: urn:nbn:se:su:diva-185337DOI: 10.7554/eLife.58362ISI: 000563031000001PubMedID: 32812867OAI: oai:DiVA.org:su-185337DiVA, id: diva2:1506659
Tilgjengelig fra: 2020-12-03 Laget: 2020-12-03 Sist oppdatert: 2023-03-16bibliografisk kontrollert
Inngår i avhandling
1. Structural investigation of human mitochondrial translation and off-target antibiotic binding
Åpne denne publikasjonen i ny fane eller vindu >>Structural investigation of human mitochondrial translation and off-target antibiotic binding
2023 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Human mitochondrial translation machinery has evolved to translate 13 mitochondrial mRNAs encoding components of the oxidative phosphorylation pathway responsible for ATP production. The structural basis of human mitochondrial translation is distinct from the canonical bacterial and cytosolic translation systems. Further, mutations affecting mitochondrial protein synthesis disrupt ATP production resulting in myopathies and neurodegenerative diseases. Structural studies have identified the core components of the human mitoribosome and some of its associated translation factors but several important aspects such as the role of mito-specific proteins in translation, rRNA modifications, composition of its ultrastructure including ions, small molecule co-factors, and solvent content, remain poorly understood. Importantly, several important antibiotics that target bacterial translation also affect mitochondrial translation, thereby causing adverse effects in patients. Understanding the mechanism of off-target antibiotic binding to the mitoribosome could help in designing better antibiotics. In this work, we use electron cryo-microscopy to determine the structures of the human mitoribosome in complex with ligands: mRNA/tRNA and translation activators such as LRPPRC-SLIRP. This allows us to explore the structural basis of mitochondrial translation, identifying the roles of mito-specific protein elements in tRNA and mRNA binding and recruitment (Papers 1 and 2). We determine a 2.2 Å resolution structure of the human mitoribosome and a 2.4 Å resolution structure of the mitoribosomal small subunit in complex with the tuberculosis drug, streptomycin. Together, the structures represent the most detailed and complete models for the human mitoribosome, revealing rRNA and protein modifications; several novel small molecule cofactors: 2Fe-2S clusters, polyamines and nucleotides and mechanisms of antibiotic binding (Papers 3 and 4).

sted, utgiver, år, opplag, sider
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2023. s. 65
Emneord
Mitochondrial translation, mitoribosome, electron cryo-microscopy, LRPPRC-SLIRP, antibiotics, streptomycin
HSV kategori
Forskningsprogram
biofysik
Identifikatorer
urn:nbn:se:su:diva-215504 (URN)978-91-8014-240-3 (ISBN)978-91-8014-241-0 (ISBN)
Disputas
2023-04-24, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 14:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2023-03-30 Laget: 2023-03-16 Sist oppdatert: 2023-03-24bibliografisk kontrollert

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