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Cbp3-Cbp6 interacts with the yeast mitochondrial ribosomal tunnel exit and promotes cytochrome b synthesis and assembly
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2011 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 193, no 6, 1101-1114 p.Article in journal (Refereed) Published
Abstract [en]

Mitochondria contain their own genetic system to express a small number of hydrophobic polypeptides, including cytochrome b, an essential subunit of the bc(1) complex of the respiratory chain. In this paper, we show in yeast that Cbp3, a bc(1) complex assembly factor, and Cbp6, a regulator of cytochrome b translation, form a complex that associates with the polypeptide tunnel exit of mitochondrial ribosomes and that exhibits two important functions in the biogenesis of cytochrome b. On the one hand, the interaction of Cbp3 and Cbp6 with mitochondrial ribosomes is necessary for efficient translation of cytochrome b messenger ribonucleic acid or transcript. On the other hand, the Cbp3-Cbp6 complex interacts directly with newly synthesized cytochrome b in an assembly intermediate that is not ribosome bound and that contains the assembly factor Cbp4. Our results suggest that synthesis of cytochrome b occurs preferentially on those ribosomes that have the Cbp3-Cbp6 complex bound to their tunnel exit, an arrangement that may ensure tight coordination of cytochrome b synthesis and assembly.

Place, publisher, year, edition, pages
2011. Vol. 193, no 6, 1101-1114 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-67580DOI: 10.1083/jcb.201103132ISI: 000291586400014OAI: oai:DiVA.org:su-67580DiVA: diva2:470568
Note
authorCount :8Available from: 2011-12-29 Created: 2011-12-29 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Early steps in the biogenesis of the bc1 complex in yeast mitochondria: The role of the Cbp3-Cbp6 complex in cytochrome b synthesis and assembly
Open this publication in new window or tab >>Early steps in the biogenesis of the bc1 complex in yeast mitochondria: The role of the Cbp3-Cbp6 complex in cytochrome b synthesis and assembly
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The inner membrane of mitochondria harbors the complexes of the respiratory chain and the ATP synthase, which perform the key metabolic process oxidative phosphorylation. These complexes are composed of subunits from two different genetic origins: the majority of constituents is synthesized on cytosolic ribosomes and imported into mitochondria, but a handful of proteins, which represent core catalytic subunits, are encoded in the organellar DNA and translated on mitochondrial ribosomes. Using yeast as a model organism, I investigated the mitochondrial ribosomal tunnel exit, the region of the ribosome where the nascent chain emerges and that in cytosolic ribosomes serves as a platform to bind biogenesis factors that help the newly synthesized protein to mature. This study provided insights into the structural composition of this important site of mitochondrial ribosomes and revealed the positioning of Cbp3 at the tunnel exit region, a chaperone required specifically for the assembly of the bc1 complex. In my further work I found that Cbp3 structurally and functionally forms a tight complex with Cbp6 and that this complex exhibits fundamental roles in the biogenesis of cytochrome b, the mitochondrially encoded subunit of the bc1 complex. Bound to the ribosome, Cbp3-Cbp6 stimulates translation of the cytochrome b mRNA (COB mRNA). Cbp3-Cbp6 then binds the fully synthesized cytochrome b, thereby stabilizing and guiding it further through bc1 complex assembly. The next steps involve the recruitment of the assembly factor Cbp4 to the Cbp3-Cbp6/cytochrome b complex and presumably acquisition of two redox active heme b cofactors. During further assembly Cbp3-Cbp6 is released from cytochrome b, can again bind to the ribosome and activate further rounds of COB mRNA translation. The dual role of Cbp3-Cbp6 in both translation and assembly allows the complex to act as a regulatory switch to modulate the level of cytochrome b synthesis in response to the bc1 complex assembly process.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2012. 54 p.
Keyword
mitochondria, respiratory chain assembly, bc1 complex, mitochondrial gene expression, translational regulation, hemylation
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-81033 (URN)978-91-7447-534-0 (ISBN)
Public defence
2012-12-07, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2012-11-15 Created: 2012-10-08 Last updated: 2012-11-07Bibliographically approved
2. Organization of mitochondrial gene expression in yeast: Specific features of organellar protein synthesis
Open this publication in new window or tab >>Organization of mitochondrial gene expression in yeast: Specific features of organellar protein synthesis
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mitochondria contain their own genetic system, encoding key subunits of the oxidative phosphorylation system. These subunits are expressed by an organelle-specific gene expression machinery. This work revealed a number of fundamental aspects of mitochondrial gene expression and provides evidence that this process is organized in a unique and organelle-specific manner which likely evolved to optimize protein synthesis and assembly in mitochondria. Most importantly, improving the experimental handling of ribosomes we could show that mitochondrial ribosomes are organized in large assemblies that we termed MIOREX complexes. Ribosomes present in these complexes organize gene expression by recruiting multiple factors required for post-transcriptional steps. In addition, we could reveal mechanisms by which ribosome-interactor complexes modulate and coordinate the expression and assembly of the respiratory chain subunits. For example we showed that the Cbp3-Cbp6 complex binds to the ribosome in proximity to the tunnel exit to coordinate synthesis and assembly of cytochrome b. This location perfectly positions Cbp3-Cbp6 for direct binding to newly synthesized cytochrome b and permits Cbp3-Cbp6 to establish a feedback loop that allows modulation of cytochrome b synthesis in response to assembly efficiency. Likewise the interaction of the membrane-anchor proteins Mba1 and Mdm38 with the tunnel exit region enables them to participate in the translation of the two intron-encoding genes COX1 and COB in addition to their role in membrane insertion.  In summary, work presented in this thesis shows that mitochondrial gene expression is a highly organized and regulated process. The concepts and technical innovations will facilitate the elucidation of many additional and important aspects and therefore contribute to the general understanding of how proteins are synthesized in mitochondria.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2014. 73 p.
Keyword
Mitochondria, translation, bc1 complex, ribosome, gene expression
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-107568 (URN)978-91-7447-985-0 (ISBN)
Public defence
2014-11-07, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2014-10-16 Created: 2014-09-19 Last updated: 2014-11-10Bibliographically approved

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