| dc.contributor.advisor | Richter-Dennerlein, Ricarda Dr. | |
| dc.contributor.author | Lavdovskaia, Elena | |
| dc.date.accessioned | 2022-05-03T13:47:55Z | |
| dc.date.available | 2022-05-10T00:50:12Z | |
| dc.date.issued | 2022-05-03 | |
| dc.identifier.uri | http://resolver.sub.uni-goettingen.de/purl?ediss-11858/14024 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-9223 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| dc.subject.ddc | 572 | de |
| dc.title | The role of GTPases in human mitochondrial ribosome biogenesis | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Urlaub, Henning Prof. Dr. | |
| dc.date.examination | 2021-07-27 | de |
| dc.description.abstracteng | Mitochondria are essential organelles of eukaryotic cells, which produce the vast majority of the cellular ATP via oxidative phosphorylation (OXPHOS). The mitochondrial gene expression machinery contributes to the formation of the OXPHOS complexes by providing 13 core protein components synthesized by dedicated mitochondrial ribosomes (mitoribosomes). Despite the recent progress in our understanding of the mitoribosome structure and function, the assembly pathway of this ribonucleoprotein complex remains elusive. Furthermore, an increasing number of diseases are linked to defects in the mitochondrial translation apparatus but the molecular basis of these disorders is still unknown.
Mitoribosome biogenesis is facilitated by nuclear-encoded auxiliary factors required for the proper assembly and folding of RNAs and mitoribosomal proteins. The human genome encodes numeral GTP-binding proteins that are involved into the biogenesis of the mitoribosomal particles. However, the exact molecular functions of these proteins remain largely unknown. Using the combination of biochemical, mass spectrometry and structural biology methods, we identified the members of the Obg/HflX GTPases superfamily GTPBP6 and GTPBP10 as factors required for late stages of mitoribosomal large subunit (mtLSU) assembly. We showed that GTPBP10 associates with the other factors, including proteins required for the 16S rRNA processing, mitochondrial RNA granule components and late mitoribosome assembly factors such as the MALSU1 module and the MTERF4-NSUN4 complex to facilitate mtLSU maturation. Altogether, our data suggest that GTPBP10 is essential for mitoribosome biogenesis and thus for mitochondrial translation and OXPHOS complexes formation.
The other GTPase, GTPBP6 is homologous to bacterial HflX protein. We have shown that in humans GTPBP6 retains its conserved function as a ribosome recycling factor. Surprisingly, in contrast to its bacterial counterpart, GTPBP6 does fulfill an additional role as a mitoribosome biogenesis factor and is essential for cell growth and mitochondrial gene expression under physiological conditions. GTPBP6 ablation abolishes mitoribosome formation associated with the accumulation of the nearly matured subunits, thereby leading to mitochondrial translation deficiency. Loss of GTPBP6 stalls mtLSU maturation at a very late assembly stage when all of the mitoribosomal proteins are incorporated. Cryo-electron microscopy approach revealed that GTPBP6 is required for the final folding of the catalytic core of the ribosome – the peptidyl transferase center (PTC). Additionally, the analysis disclosed an interplay of the assembly factors during the PTC maturation. Thus, we have shown that GTPBP5 cooperates with MTERF4-NSUN4 complex to promote the PTC folding. In summary, our data has revealed that GTPBP6 and GTPBP10 coordinate late steps of the PTC maturation in collaboration with the other assembly factors. This mode of the mitoribosome biogenesis is reminiscent of other ribosomes and highlights the evolutionary conserved mechanism of involved GTPases. Moreover, we have disclosed an alternative pathway for mitoribosome recycling mediated by GTPBP6. | de |
| dc.contributor.coReferee | Ficner, Ralf Prof. Dr. | |
| dc.subject.eng | Mitochondrial ribosome | de |
| dc.subject.eng | Mitochondrial ribosome biogenesis | de |
| dc.subject.eng | Ribonucleoprotein | de |
| dc.subject.eng | Ribosome | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-ediss-14024-0 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2022-05-10 | de |
| dc.identifier.ppn | 1800989938 | |
| dc.creator.birthname | Shirokolobova | de |