| 1. |
- Aibara, Shintaro, et al.
(författare)
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Rapid Isolation of the Mitoribosome from HEK Cells
- 2018
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Ingår i: Journal of Visualized Experiments. - : MyJove Corporation. - 1940-087X. ; :140
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Tidskriftsartikel (refereegranskat)abstract
- The human mitochondria possess a dedicated set of ribosomes (mitoribosomes) that translate 13 essential protein components of the oxidative phosphorylation complexes encoded by the mitochondria! genome. Since all proteins synthesized by human mitoribosomes are integral membrane proteins, human mitoribosomes are tethered to the mitochondrial inner membrane during translation. Compared to the cytosolic ribosome the mitoribosome has a sedimentation coefficient of 55S, half the rRNA content, no 5S rRNA and 36 additional proteins. Therefore, a higher protein-to-RNA ratio and an atypical structure make the human mitoribosome substantially distinct from its cytosolic counterpart. Despite the central importance of the mitoribosome to life, no protocols were available to purify the intact complex from human cell lines. Traditionally, mitoribosomes were isolated from mitochondria-rich animal tissues that required kilograms of starting material. We reasoned that mitochondria in dividing HEK293-derived human cells grown in nutrient-rich expression medium would have an active mitochondrial translation, and, therefore, could be a suitable source of material for the structural and biochemical studies of the mitoribosome. To investigate its structure, we developed a protocol for large-scale purification of intact mitoribosomes from HEK cells. Herein, we introduce nitrogen cavitation method as a faster, less labor-intensive and more efficient alternative to traditional mechanical shear-based methods for cell lysis. This resulted in preparations of the mitoribosome that allowed for its structural determination to high resolution, revealing the composition of the intact human mitoribosome and its assembly intermediates. Here, we follow up on this work and present an optimized and more cost-effective method requiring only similar to 10(10) cultured HEK cells. The method can be employed to purify human mitoribosomal translating complexes, mutants, quality control assemblies and mitoribosomal subunits intermediates. The purification can be linearly scaled up tenfold if needed, and also applied to other types of cells.
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| 2. |
- Aibara, Shintaro, et al.
(författare)
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Structural basis of mitochondrial translation
- 2020
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Ingår i: eLIFE. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Amunts, Alexey
(författare)
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The revolution evolution
- 2022
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Ingår i: Nature Plants. - : Springer Science and Business Media LLC. - 2055-0278. ; 8:1, s. 14-17
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Bigalke, Janna M., et al.
(författare)
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Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain
- 2019
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 5:7
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Tidskriftsartikel (refereegranskat)abstract
- Signaling through the receptor tyrosine kinase RET is essential during normal development. Both gain- and loss-of-function mutations are involved in a variety of diseases, yet the molecular details of receptor activation have remained elusive. We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFR alpha 2 and determined its structure at 5.7-angstrom resolution by cryo-EM. The proteins form an assembly through RET-GFR alpha 2 and RET-NRTN interfaces. Two key interaction points required for RET extracellular domain binding were observed: (i) the calcium-binding site in RET that contacts GFR alpha 2 domain 3 and (ii) the RET cysteine-rich domain interaction with NRTN. The structure highlights the importance of the RET cysteine-rich domain and allows proposition of a model to explain how complex formation leads to RET receptor dimerization and its activation. This provides a framework for targeting RET activity and for further exploration of mechanisms underlying neurological diseases.
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| 5. |
- Brown, Alan, et al.
(författare)
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Structures of the human mitochondrial ribosome in native states of assembly
- 2017
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Ingår i: Nature Structural & Molecular Biology. - : Springer Science and Business Media LLC. - 1545-9993 .- 1545-9985. ; 24:10, s. 866-869
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Tidskriftsartikel (refereegranskat)abstract
- Mammalian mitochondrial ribosomes (mitoribosomes) have less rRNA content and 36 additional proteins compared with the evolutionarily related bacterial ribosome. These differences make the assembly of mitoribosomes more complex than the assembly of bacterial ribosomes, but the molecular details of mitoribosomal biogenesis remain elusive. Here, we report the structures of two late-stage assembly intermediates of the human mitoribosomal large subunit (mt-LSU) isolated from a native pool within a human cell line and solved by cryo-EM to similar to 3-angstrom resolution. Comparison of the structures reveals insights into the timing of rRNA folding and protein incorporation during the final steps of ribosomal maturation and the evolutionary adaptations that are required to preserve biogenesis after the structural diversification of mitoribosomes. Furthermore, the structures redefine the ribosome silencing factor (RsfS) family as multifunctional biogenesis factors and identify two new assembly factors (L0R8F8 and mt-ACP) not previously implicated in mitoribosomal biogenesis.
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| 6. |
- Bugiardini, Enrico, et al.
(författare)
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MRPS25 mutations impair mitochondrial translation and cause encephalomyopathy
- 2019
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 28:16, s. 2711-2719
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial disorders are clinically and genetically heterogeneous and are associated with a variety of disease mechanisms. Defects of mitochondrial protein synthesis account for the largest subgroup of disorders manifesting with impaired respiratory chain capacity; yet, only a few have been linked to dysfunction in the protein components of the mitochondrial ribosomes. Here, we report a subject presenting with dyskinetic cerebral palsy and partial agenesis of the corpus callosum, while histochemical and biochemical analyses of skeletal muscle revealed signs of mitochondrial myopathy. Using exome sequencing, we identified a homozygous variant c.215C>T in MRPS25, which encodes for a structural component of the 28S small subunit of the mitochondrial ribosome (mS25). The variant segregated with the disease and substitutes a highly conserved proline residue with leucine (p.P72L) that, based on the high-resolution structure of the 28S ribosome, is predicted to compromise inter-protein contacts and destabilize the small subunit. Concordant with the in silico analysis, patient's fibroblasts showed decreased levels of MRPS25 and other components of the 28S subunit. Moreover, assembled 28S subunits were scarce in the fibroblasts with mutant mS25 leading to impaired mitochondrial translation and decreased levels of multiple respiratory chain subunits. Crucially, these abnormalities were rescued by transgenic expression of wild-type MRPS25 in the mutant fibroblasts. Collectively, our data demonstrate the pathogenicity of the p.P72L variant and identify MRPS25 mutations as a new cause of mitochondrial translation defect.
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| 7. |
- Chen, Ming, et al.
(författare)
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Distinct structural modulation of photosystem I and lipid environment stabilizes its tetrameric assembly
- 2020
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Ingår i: Nature Plants. - : Springer Science and Business Media LLC. - 2055-026X .- 2055-0278. ; 6:3, s. 314-
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Tidskriftsartikel (refereegranskat)abstract
- Photosystem I (PSI) is able to form different oligomeric states across various species. To reveal the structural basis for PSI dimerization and tetramerization, we structurally investigated PSI from the cyanobacterium Anabaena. This revealed a disrupted trimerization domain due to lack of the terminal residues of PsaL in the lumen, which resulted in PSI dimers with loose connections between monomers and weaker energy-coupled chlorophylls than in the trimer. At the dimer surface, specific phospholipids, cofactors and interactions in combination facilitated recruitment of another dimer to form a tetramer. Taken together, the relaxed luminal connections and lipid specificity at the dimer interface account for membrane curvature. PSI tetramer assembly appears to increase the surface area of the thylakoid membrane, which would contribute to PSI crowding. Photosystem I from the cyanobacterium Anabaena has a disrupted trimerization domain resulting in dimers with loose connections between monomers. Phospholipids and cofactors at the dimer surface facilitate further dimerization to form a tetramer.
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| 8. |
- Cottilli, Patrick, et al.
(författare)
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Cryo-EM structure and rRNA modification sites of a plant ribosome
- 2022
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Ingår i: Plant Communications. - : Elsevier BV. - 2590-3462. ; 3:5
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Tidskriftsartikel (refereegranskat)abstract
- Protein synthesis in crop plants contributes to the balance of food and fuel on our planet, which influences human metabolic activity and lifespan. Protein synthesis can be regulated with respect to changing environmental cues via the deposition of chemical modifications into rRNA. Here, we present the structure of a plant ribosome from tomato and a quantitative mass spectrometry analysis of its rRNAs. The study reveals fine features of the ribosomal proteins and 71 plant-specific rRNA modifications, and it re-annotates 30 rRNA residues in the available sequence. At the protein level, isoAsp is found in position 137 of uS11, and a zinc finger previously believed to be universal is missing from eL34, suggesting a lower effect of zinc deficiency on protein synthesis in plants. At the rRNA level, the plant ribosome differs markedly from its human counterpart with respect to the spatial distribution of modifications. Thus, it represents an additional layer of gene expression regulation, highlighting the molecular signature of a plant ribosome. The results provide a reference model of a plant ribosome for structural studies and an accurate marker for molecular ecology.
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| 9. |
- Desai, Nirupa, et al.
(författare)
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The structure of the yeast mitochondrial ribosome
- 2017
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 355:6324, s. 528-531
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondria have specialized ribosomes (mitoribosomes) dedicated to the expression of the genetic information encoded by their genomes. Here, using electron cryomicroscopy, we have determined the structure of the 75-component yeast mitoribosome to an overall resolution of 3.3 angstroms. The mitoribosomal small subunit has been built de novo and includes 15S ribosomal RNA (rRNA) and 34 proteins, including 14 without homologs in the evolutionarily related bacterial ribosome. Yeast-specific rRNA and protein elements, including the acquisition of a putatively active enzyme, give the mitoribosome a distinct architecture compared to the mammalian mitoribosome. At an expanded messenger RNA channel exit, there is a binding platform for translational activators that regulate translation in yeast but not mammalian mitochondria. The structure provides insights into the evolution and species-specific specialization of mitochondrial translation.
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| 10. |
- Forsberg, Björn O., et al.
(författare)
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Cryo-EM reconstruction of the chlororibosome to 3.2 angstrom resolution within 24 h
- 2017
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Ingår i: IUCrJ. - 2052-2525. ; 4, s. 723-727
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Tidskriftsartikel (refereegranskat)abstract
- The introduction of direct detectors and the automation of data collection in cryo-EM have led to a surge in data, creating new opportunities for advancing computational processing. In particular, on-the-fly workflows that connect data collection with three-dimensional reconstruction would be valuable for more efficient use of cryo-EM and its application as a sample-screening tool. Here, accelerated on-the-fly analysis is reported with optimized organization of the data-processing tools, image acquisition and particle alignment that make it possible to reconstruct the three-dimensional density of the 70S chlororibosome to 3.2 angstrom resolution within 24 h of tissue harvesting. It is also shown that it is possible to achieve even faster processing at comparable quality by imposing some limits to data use, as illustrated by a 3.7 angstrom resolution map that was obtained in only 80 min on a desktop computer. These on-the-fly methods can be employed as an assessment of data quality from small samples and extended to high-throughput approaches.
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| 11. |
- Gahura, Ondřej, et al.
(författare)
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An ancestral interaction module promotes oligomerization in divergent mitochondrial ATP synthases
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial ATP synthase forms stable dimers arranged into oligomeric assemblies that generate the inner-membrane curvature essential for efficient energy conversion. Here, we report cryo-EM structures of the intact ATP synthase dimer from Trypanosoma brucei in ten different rotational states. The model consists of 25 subunits, including nine lineage-specific, as well as 36 lipids. The rotary mechanism is influenced by the divergent peripheral stalk, conferring a greater conformational flexibility. Proton transfer in the lumenal half-channel occurs via a chain of five ordered water molecules. The dimerization interface is formed by subunit-g that is critical for interactions but not for the catalytic activity. Although overall dimer architecture varies among eukaryotes, we find that subunit-g together with subunit-e form an ancestral oligomerization motif, which is shared between the trypanosomal and mammalian lineages. Therefore, our data defines the subunit-g/e module as a structural component determining ATP synthase oligomeric assemblies. Mitochondrial ATP synthase assemble into oligomers. Here, authors resolve the structure of trypanosomal ATP synthase, showing that its dimerization is essential for function and evolutionary conserved.
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| 12. |
- Itoh, Yuzuru, et al.
(författare)
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Analysis of translating mitoribosome reveals functional characteristics of translation in mitochondria of fungi
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Mitoribosomes are specialized protein synthesis machineries in mitochondria. However, how mRNA binds to its dedicated channel, and tRNA moves as the mitoribosomal subunit rotate with respect to each other is not understood. We report models of the translating fungal mitoribosome with mRNA, tRNA and nascent polypeptide, as well as an assembly intermediate. Nicotinamide adenine dinucleotide (NAD) is found in the central protuberance of the large subunit, and the ATPase inhibitory factor 1 (IF1) in the small subunit. The models of the active mitoribosome explain how mRNA binds through a dedicated protein platform on the small subunit, tRNA is translocated with the help of the protein mL108, bridging it with L1 stalk on the large subunit, and nascent polypeptide paths through a newly shaped exit tunnel involving a series of structural rearrangements. An assembly intermediate is modeled with the maturation factor Atp25, providing insight into the biogenesis of the mitoribosomal large subunit and translation regulation.
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| 13. |
- Itoh, Yuzuru, et al.
(författare)
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Mechanism of membrane-tethered mitochondrial protein synthesis
- 2021
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 371:6531, s. 846-849
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial ribosomes (mitoribosomes) are tethered to the mitochondrial inner membrane to facilitate the cotranslational membrane insertion of the synthesized proteins. We report cryo-electron microscopy structures of human mitoribosomes with nascent polypeptide, bound to the insertase oxidase assembly 1-like (OXA1L) through three distinct contact sites. OXA1L binding is correlated with a series of conformational changes in the mitoribosomal large subunit that catalyze the delivery of newly synthesized polypeptides. The mechanism relies on the folding of mL45 inside the exit tunnel, forming two specific constriction sites that would limit helix formation of the nascent chain. A gap is formed between the exit and the membrane, making the newly synthesized proteins accessible. Our data elucidate the basis by which mitoribosomes interact with the OXA1L insertase to couple protein synthesis and membrane delivery.
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| 14. |
- Itoh, Yuzuru, et al.
(författare)
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Mechanism of mitoribosomal small subunit biogenesis and preinitiation
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 606, s. 603-608
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Tidskriftsartikel (refereegranskat)abstract
- Mitoribosomes are essential for the synthesis and maintenance of bioenergetic proteins. Here we use cryo-electron microscopy to determine a series of the small mitoribosomal subunit (SSU) intermediates in complex with auxiliary factors, revealing a sequential assembly mechanism. The methyltransferase TFB1M binds to partially unfolded rRNA h45 that is promoted by RBFA, while the mRNA channel is blocked. This enables binding of METTL15 that promotes further rRNA maturation and a large conformational change of RBFA. The new conformation allows initiation factor mtIF3 to already occupy the subunit interface during the assembly. Finally, the mitochondria-specific ribosomal protein mS37 (ref. 1) outcompetes RBFA to complete the assembly with the SSU–mS37–mtIF3 complex2 that proceeds towards mtIF2 binding and translation initiation. Our results explain how the action of step-specific factors modulate the dynamic assembly of the SSU, and adaptation of a unique protein, mS37, links the assembly to initiation to establish the catalytic human mitoribosome.
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| 15. |
- Itoh, Yuzuru, et al.
(författare)
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Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules
- 2022
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Ingår i: eLIFE. - 2050-084X. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- The mitoribosome regulates cellular energy production, and its dysfunction is associated with aging. Inhibition of the mitoribosome can be caused by off-target binding of antimicrobial drugs and was shown to be coupled with a bilateral decreased visual acuity. Previously, we reported mitochondria-specific protein aspects of the mitoribosome, and in this article we present a 2.4-Å resolution structure of the small subunit in a complex with the anti-tuberculosis drug streptomycin that reveals roles of non-protein components. We found iron–sulfur clusters that are coordinated by different mitoribosomal proteins, nicotinamide adenine dinucleotide (NAD) associated with rRNA insertion, and posttranslational modifications. This is the first evidence of inter-protein coordination of iron–sulfur, and the finding of iron–sulfur clusters and NAD as fundamental building blocks of the mitoribosome directly links to mitochondrial disease and aging. We also report details of streptomycin interactions, suggesting that the mitoribosome-bound streptomycin is likely to be in hydrated gem-diol form and can be subjected to other modifications by the cellular milieu. The presented approach of adding antibiotics to cultured cells can be used to define their native structures in a bound form under more physiological conditions, and since streptomycin is a widely used drug for treatment, the newly resolved features can serve as determinants for targeting.
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| 16. |
- Khawaja, Anas, et al.
(författare)
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Distinct pre-initiation steps in human mitochondrial translation
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Translation initiation in human mitochondria relies upon specialized mitoribosomes and initiation factors, mtIF2 and mtIF3, which have diverged from their bacterial counterparts. Here we report two distinct mitochondrial pre-initiation assembly steps involving those factors. Single-particle cryo-EM revealed that in the first step, interactions between mitochondria-specific protein mS37 and mtIF3 keep the small mitoribosomal subunit in a conformation favorable for a subsequent accommodation of mtIF2 in the second step. Combination with fluorescence cross-correlation spectroscopy analyses suggests that mtIF3 promotes complex assembly without mRNA or initiator tRNA binding, where exclusion is achieved by the N-terminal and C-terminal domains of mtIF3. Finally, the association of large mitoribosomal subunit is required for initiator tRNA and leaderless mRNA recruitment to form a stable initiation complex. These data reveal fundamental aspects of mammalian protein synthesis that are specific to mitochondria.
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| 17. |
- Kock Flygaard, Rasmus, et al.
(författare)
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Type III ATP synthase is a symmetry-deviated dimer that induces membrane curvature through tetramerization
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial ATP synthases form functional homodimers to induce cristae curvature that is a universal property of mitochondria. To expand on the understanding of this fundamental phenomenon, we characterized the unique type III mitochondrial ATP synthase in its dimeric and tetrameric form. The cryo-EM structure of a ciliate ATP synthase dimer reveals an unusual U-shaped assembly of 81 proteins, including a substoichiometrically bound ATPTT2, 40 lipids, and co-factors NAD and CoQ. A single copy of subunit ATPTT2 functions as a membrane anchor for the dimeric inhibitor IF1. Type III specific linker proteins stably tie the ATP synthase monomers in parallel to each other. The intricate dimer architecture is scaffolded by an extended subunit-a that provides a template for both intra- and inter-dimer interactions. The latter results in the formation of tetramer assemblies, the membrane part of which we determined to 3.1 angstrom resolution. The structure of the type III ATP synthase tetramer and its associated lipids suggests that it is the intact unit propagating the membrane curvature.
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| 18. |
- Matzov, Donna, et al.
(författare)
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The cryo-EM structure of hibernating 100S ribosome dimer from pathogenic Staphylococcus aureus
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Formation of 100S ribosome dimer is generally associated with translation suppression in bacteria. Trans-acting factors ribosome modulation factor (RMF) and hibernating promoting factor (HPF) were shown to directly mediate this process in E. coli. Gram-positive S. aureus lacks an RMF homolog and the structural basis for its 100S formation was not known. Here we report the cryo-electron microscopy structure of the native 100S ribosome from S. aureus, revealing the molecular mechanism of its formation. The structure is distinct from previously reported analogs and relies on the HPF C-terminal extension forming the binding platform for the interactions between both of the small ribosomal subunits. The 100S dimer is formed through interactions between rRNA h26, h40, and protein uS2, involving conformational changes of the head as well as surface regions that could potentially prevent RNA polymerase from docking to the ribosome.
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| 19. |
- Mühleip, Alexander, et al.
(författare)
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ATP synthase hexamer assemblies shape cristae of Toxoplasma mitochondria
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial ATP synthase plays a key role in inducing membrane curvature to establish cristae. In Apicomplexa causing diseases such as malaria and toxoplasmosis, an unusual cristae morphology has been observed, but its structural basis is unknown. Here, we report that the apicomplexan ATP synthase assembles into cyclic hexamers, essential to shape their distinct cristae. Cryo-EM was used to determine the structure of the hexamer, which is held together by interactions between parasite-specific subunits in the lumenal region. Overall, we identified 17 apicomplexan-specific subunits, and a minimal and nuclear-encoded subunit-a. The hexamer consists of three dimers with an extensive dimer interface that includes bound cardiolipins and the inhibitor IF1. Cryo-ET and subtomogram averaging revealed that hexamers arrange into ~20-megadalton pentagonal pyramids in the curved apical membrane regions. Knockout of the linker protein ATPTG11 resulted in the loss of pentagonal pyramids with concomitant aberrantly shaped cristae. Together, this demonstrates that the unique macromolecular arrangement is critical for the maintenance of cristae morphology in Apicomplexa.
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| 20. |
- Mühleip, Alexander, et al.
(författare)
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Structural basis of mitochondrial membrane bending by the I–II–III2–IV2 supercomplex
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 615:7954, s. 934-938
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial energy conversion requires an intricate architecture of the inner mitochondrial membrane. Here we show that a supercomplex containing all four respiratory chain components contributes to membrane curvature induction in ciliates. We report cryo-electron microscopy and cryo-tomography structures of the supercomplex that comprises 150 different proteins and 311 bound lipids, forming a stable 5.8-MDa assembly. Owing to subunit acquisition and extension, complex I associates with a complex IV dimer, generating a wedge-shaped gap that serves as a binding site for complex II. Together with a tilted complex III dimer association, it results in a curved membrane region. Using molecular dynamics simulations, we demonstrate that the divergent supercomplex actively contributes to the membrane curvature induction and tubulation of cristae. Our findings highlight how the evolution of protein subunits of respiratory complexes has led to the I–II–III2–IV2 supercomplex that contributes to the shaping of the bioenergetic membrane, thereby enabling its functional specialization
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| 21. |
- Mühleip, Alexander, et al.
(författare)
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Structure of a mitochondrial ATP synthase with bound native cardiolipin
- 2019
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Ingår i: eLIFE. - 2050-084X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- The mitochondrial ATP synthase fuels eukaryotic cells with chemical energy. Here we report the cryo-EM structure of a divergent ATP synthase dimer from mitochondria of Euglena gracilis, a member of the phylum Euglenozoa that also includes human parasites. It features 29 different subunits, 8 of which are newly identified. The membrane region was determined to 2.8 angstrom resolution, enabling the identification of 37 associated lipids, including 25 cardiolipins, which provides insight into protein-lipid interactions and their functional roles. The rotor-stator interface comprises four membrane-embedded horizontal helices, including a distinct subunit a. The dimer interface is formed entirely by phylum-specific components, and a peripherally associated subcomplex contributes to the membrane curvature. The central and peripheral stalks directly interact with each other. Last, the ATPase inhibitory factor 1 (IF1) binds in a mode that is different from human, but conserved in Trypanosomatids.
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| 22. |
- Naschberger, Andreas, et al.
(författare)
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Algal photosystem I dimer and high-resolution model of PSI-plastocyanin complex
- 2022
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Ingår i: Nature Plants. - : Springer Science and Business Media LLC. - 2055-0278. ; 8:10, s. 1191-1201
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Tidskriftsartikel (refereegranskat)abstract
- Photosystem I (PSI) enables photo-electron transfer and regulates photosynthesis in the bioenergetic membranes of cyanobacteria and chloroplasts. Being a multi-subunit complex, its macromolecular organization affects the dynamics of photosynthetic membranes. Here we reveal a chloroplast PSI from the green alga Chlamydomonas reinhardtii that is organized as a homodimer, comprising 40 protein subunits with 118 transmembrane helices that provide scaffold for 568 pigments. Cryogenic electron microscopy identified that the absence of PsaH and Lhca2 gives rise to a head-to-head relative orientation of the PSI–light-harvesting complex I monomers in a way that is essentially different from the oligomer formation in cyanobacteria. The light-harvesting protein Lhca9 is the key element for mediating this dimerization. The interface between the monomers is lacking PsaH and thus partially overlaps with the surface area that would bind one of the light-harvesting complex II complexes in state transitions. We also define the most accurate available PSI–light-harvesting complex I model at 2.3 Å resolution, including a flexibly bound electron donor plastocyanin, and assign correct identities and orientations to all the pigments, as well as 621 water molecules that affect energy transfer pathways.
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| 23. |
- Naschberger, Andreas, et al.
(författare)
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Structure of plant photosystem I in a native assembly state defines PsaF as a regulatory checkpoint
- 2024
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Ingår i: Nature plants. - 2055-026X.
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Tidskriftsartikel (refereegranskat)abstract
- Plant photosystem I (PSI) consists of at least 13 nuclear-encoded and 4 chloroplast-encoded subunits that together act as a sunlight-driven oxidoreductase. Here we report the structure of a PSI assembly intermediate that we isolated from greening oat seedlings. The assembly intermediate shows an absence of at least eight subunits, including PsaF and LHCI, and lacks photoreduction activity. The data show that PsaF is a regulatory checkpoint that promotes the assembly of LHCI, effectively coupling biogenesis to function. This study reports the structure of a photosystem I assembly intermediate isolated from greening oat seedlings. It defines PsaF as a regulatory checkpoint promoting the association of LHCI that couples biogenesis to function.
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| 24. |
- Nirwan, Neha, et al.
(författare)
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Structure-based mechanism for activation of the AAA plus GTPase McrB by the endonuclease McrC
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The AAA+ GTPase McrB powers DNA cleavage by the endonuclease McrC. The GTPase itself is activated by McrC. The architecture of the GTPase and nuclease complex, and the mechanism of their activation remained unknown. Here, we report a 3.6 angstrom structure of a GTPase-active and DNA-binding deficient construct of McrBC. Two hexameric rings of McrB are bridged by McrC dimer. McrC interacts asymmetrically with McrB protomers and inserts a stalk into the pore of the ring, reminiscent of the gamma subunit complexed to alpha(3)beta(3) of F-1-ATPase. Activation of the GTPase involves conformational changes of residues essential for hydrolysis. Three consecutive nucleotide-binding pockets are occupied by the GTP analogue 5'-guanylyl imidodiphosphate and the next three by GDP, which is suggestive of sequential GTP hydrolysis.
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| 25. |
- Ott, Martin, et al.
(författare)
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Organization and Regulation of Mitochondrial Protein Synthesis
- 2016
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Ingår i: Annual Review of Biochemistry. - : Annual Reviews. - 0066-4154 .- 1545-4509. ; 85, s. 77-101
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Forskningsöversikt (refereegranskat)abstract
- Mitochondria are essential organelles of endosymbiotic origin that are responsible for oxidative phosphorylation within eukaryotic cells. Independent evolution between species has generated mitochondrial genomes that are extremely diverse, with the composition of the vestigial genome determining their translational requirements. Typically, translation within mitochondria is restricted to a few key subunits of the oxidative phosphorylation complexes that are synthesized by dedicated ribosomes (mitoribosomes). The dramatically rearranged mitochondrial genomes, the limited set of transcripts, and the need for the synthesized proteins to coassemble with nuclear-encoded subunits have had substantial consequences for the translation machinery. Recent high-resolution cryo-electron microscopy has revealed the effect of coevolution on the mitoribosome with the mitochondrial genome. In this review, we place the new structural information in the context of the molecular mechanisms of mitochondrial translation and focus on the novel ways protein synthesis is organized and regulated in mitochondria.
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| 26. |
- Perez Boerema, Annemarie, 1991-
(författare)
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Cryo-EM Studies of Macromolecular Complexes from Photosynthetic Organisms
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Plants, algae, and cyanobacteria convert light energy into chemical energy through the process of photosynthesis, fueling the planet and making life as we know it possible. Photosystem I (PSI) is one of the main photosynthetic complexes, responsible for this process. PSI uses the energy of light to transfer electrons from the soluble electron carrier plastocyanin, on the lumenal site of the thylakoid membrane, to ferrodoxin, on the stromal site of the membrane. Thus, playing a key role in the light dependent reactions. In order to survive many photosynthetic organisms need to be able to adapt to fluctuations in light and have adapted their photosynthetic machinery accordingly. In recent years many advances have been made in electron cryo-microscopy, making it possible to visualize many previously elusive photosynthetic complexes. This has brought a wealth of information on the structural adaptations of PSI.In plants and algae, PSI is hosted by the chloroplast, a specialized organelle that houses the photosynthetic reactions. In the chloroplast, key components of PSI are synthesized by the chloroplasts own translation machinery: the chloroplast ribosome. Translation in the chloroplast is remarkable as it has to synchronize translation in two different genetic compartments as well as adapt to fluctuations in light. A glimpse of how this machinery has evolved to be able to fulfill all of these duties can be obtained from its three dimensional structure and its chloroplast specific features. However, despite all this structural information providing valuable clues as to the functioning of these systems, there are still many aspects of how they play a role that still remain unknown.
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| 27. |
- Perez-Boerema, Annemarie, et al.
(författare)
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Structure of a minimal photosystem I from the green alga Dunaliella salina
- 2020
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Ingår i: Nature plants. - : Springer Science and Business Media LLC. - 2055-026X .- 2055-0278. ; 6:3, s. 321-327
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Tidskriftsartikel (refereegranskat)abstract
- Solar energy harnessed by oxygenic photosynthesis supports most of the life forms on Earth. In eukaryotes, photosynthesis occurs in chloroplasts and is achieved by membrane-embedded macromolecular complexes that contain core and peripheral antennae with multiple pigments. The structure of photosystem I (PSI) comprises the core and light-harvesting (LHCI) complexes, which together form PSI-LHCI. Here we determined the structure of PSI-LHCI from the salt-tolerant green alga Dunaliella salina using X-ray crystallography and electron cryo-microscopy. Our results reveal a previously undescribed configuration of the PSI core. It is composed of only 7 subunits, compared with 14-16 subunits in plants and the alga Chlamydomonas reinhardtii, and forms the smallest known PSI. The LHCI is poorly conserved at the sequence level and binds to pigments that form new energy pathways, and the interactions between the individual Lhca1-4 proteins are weakened. Overall, the data indicate the PSI of D. salina represents a different type of the molecular organization that provides important information for reconstructing the plasticity and evolution of PSI. The photosystem I light-harvesting complex from the salt-tolerant green alga Dunaliella salina has a core configuration composed of only seven subunits. This unusual molecular organization could inform the reconstruction of photosystem evolution.
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| 28. |
- Perez Boerema, Annemarie, et al.
(författare)
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Structure of the chloroplast ribosome with chl-RRF and hibernation-promoting factor
- 2018
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Ingår i: Nature Plants. - : Springer Science and Business Media LLC. - 2055-026X .- 2055-0278. ; 4, s. 212-217
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Tidskriftsartikel (refereegranskat)abstract
- Oxygenic photosynthesis produces oxygen and builds a variety of organic compounds, changing the chemistry of the air, the sea and fuelling the food chain on our planet. The photochemical reactions underpinning this process in plants take place in the chloroplast. Chloroplasts evolved ~1.2 billion years ago from an engulfed primordial diazotrophic cyanobacterium, and chlororibosomes are responsible for synthesis of the core proteins driving photochemical reactions. Chlororibosomal activity is spatiotemporally coupled to the synthesis and incorporation of functionally essential co-factors, implying the presence of chloroplast-specific regulatory mechanisms and structural adaptation of the chlororibosome1,2. Despite recent structural information3,4,5,6, some of these aspects remained elusive. To provide new insights into the structural specialities and evolution, we report a comprehensive analysis of the 2.9–3.1 Å resolution electron cryo-microscopy structure of the spinach chlororibosome in complex with its recycling factor and hibernation-promoting factor. The model reveals a prominent channel extending from the exit tunnel to the chlororibosome exterior, structural re-arrangements that lead to increased surface area for translocon binding, and experimental evidence for parallel and convergent evolution of chloro- and mitoribosomes.
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| 29. |
- Petrov, Anton S., et al.
(författare)
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Structural Patching Fosters Divergence of Mitochondrial Ribosomes
- 2019
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 36:2, s. 207-219
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial ribosomes (mitoribosomes) are essential components of all mitochondria that synthesize proteins encoded by the mitochondrial genome. Unlike other ribosomes, mitoribosomes are highly variable across species. The basis for this diversity is not known. Here, we examine the composition and evolutionary history of mitoribosomes across the phylogenetic tree by combining three-dimensional structural information with a comparative analysis of the secondary structures of mitochondrial rRNAs (mt-rRNAs) and available proteomic data. We generate a map of the acquisition of structural variation and reconstruct the fundamental stages that shaped the evolution of the mitoribosomal large subunit and led to this diversity. Our analysis suggests a critical role for ablation and expansion of rapidly evolving mt-rRNA. These changes cause structural instabilities that are patched by the acquisition of pre-existing compensatory elements, thus providing opportunities for rapid evolution. This mechanism underlies the incorporation of mt-tRNA into the central protuberance of the mammalian mitoribosome, and the altered path of the polypeptide exit tunnel of the yeast mitoribosome. We propose that since the toolkits of elements utilized for structural patching differ between mitochondria of different species, it fosters the growing divergence of mitoribosomes.
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| 30. |
- Sighel, Denise, et al.
(författare)
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Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth
- 2021
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 35:4
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma stem cells (GSCs) resist current glioblastoma (GBM) therapies. GSCs rely highly on oxidative phosphorylation (OXPHOS), whose function requires mitochondrial translation. Here we explore the therapeutic potential of targeting mitochondrial translation and report the results of high-content screening with putative blockers of mitochondrial ribosomes. We identify the bacterial antibiotic quinupristin/dalfopristin (Q/D) as an effective suppressor of GSC growth. Q/D also decreases the clonogenicity of GSCs in vitro, consequently dysregulating the cell cycle and inducing apoptosis. Cryoelectron microscopy (cryo-EM) reveals that Q/D binds to the large mitoribosomal subunit, inhibiting mitochondrial protein synthesis and functionally dysregulating OXPHOS complexes. These data suggest that targeting mitochondrial translation could be explored to therapeutically suppress GSC growth in GBM and that Q/D could potentially be repurposed for cancer treatment.
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| 31. |
- Singh, Vivek, et al.
(författare)
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Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome
- 2022
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In mammalian mitochondria, mRNAs are co-transcriptionally stabilized by the protein factor LRPPRC. Here, we characterize LRPPRC as an mRNA delivery factor and report its cryo-EM structure in complex with SLIRP, mRNA and the mitoribosome. The structure shows that LRPPRC associates with the mitoribosomal proteins mS39 and the N-terminus of mS31 through recognition of eight of the LRPPRC helical repeats. Together, the proteins form a corridor for hand-off the mRNA. The mRNA is directly bound to SLIRP, which also has a stabilizing function for LRPPRC. To delineate the effect of LRPPRC on individual mitochondrial transcripts, we used an RNAseq approach, metabolic labeling and mitoribosome profiling that showed a major influence onND1, ND2, ATP6, COX1, COX2,andCOX3mRNA translation efficiency. Taken together, our data suggest that LRPPRC-SLIRP does not preexist on the mitoribosome as its structural element but rather acts in recruitment of specific mRNAs to modulate their translation. Collectively, the data define LRPPRC-SLIRP as a regulator of the mitochondrial gene expression system.
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| 32. |
- Singh, Vivek, 1988-
(författare)
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Structural investigation of human mitochondrial translation and off-target antibiotic binding
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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).
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| 33. |
- Tobiasson, Victor, et al.
(författare)
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Ciliate mitoribosome illuminates evolutionary steps of mitochondrial translation
- 2020
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Ingår i: eLIFE. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- To understand the steps involved in the evolution of translation, we used Tetrahymena thermophila, a ciliate with high coding capacity of the mitochondrial genome, as the model organism and characterized its mitochondrial ribosome (mitoribosome) using cryo-EM. The structure of the mitoribosome reveals an assembly of 94-ribosomal proteins and four-rRNAs with an additional protein mass of ~700 kDa on the small subunit, while the large subunit lacks 5S rRNA. The structure also shows that the small subunit head is constrained, tRNA binding sites are formed by mitochondria-specific protein elements, conserved protein bS1 is excluded, and bacterial RNA polymerase binding site is blocked. We provide evidence for anintrinsic protein targeting system through visualization of mitochondria-specific mL105 by the exit tunnel that would facilitate the recruitment of a nascent polypeptide. Functional protein uS3m is encoded by three complementary genes from the nucleus and mitochondrion, establishing a link between genetic drift and mitochondrial translation. Finally, we reannotated nine open reading frames in the mitochondrial genome that code for mitoribosomal proteins.
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| 34. |
- Tobiasson, Victor, et al.
(författare)
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Interconnected assembly factors regulate the biogenesis of mitoribosomal large subunit
- 2021
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Ingår i: EMBO Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 40:6
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Tidskriftsartikel (refereegranskat)abstract
- Mitoribosomes consist of ribosomal RNA and protein components, coordinated assembly of which is critical for function. We used mitoribosomes from Trypanosoma brucei with reduced RNA and increased protein mass to provide insights into the biogenesis of the mitoribosomal large subunit. Structural characterization of a stable assembly intermediate revealed 22 assembly factors, some of which have orthologues/counterparts/homologues in mammalian genomes. These assembly factors form a protein network that spans a distance of 180 angstrom, shielding the ribosomal RNA surface. The central protuberance and L7/L12 stalk are not assembled entirely and require removal of assembly factors and remodeling of the mitoribosomal proteins to become functional. The conserved proteins GTPBP7 and mt-EngA are bound together at the subunit interface in proximity to the peptidyl transferase center. A mitochondrial acyl-carrier protein plays a role in docking the L1 stalk, which needs to be repositioned during maturation. Additional enzymatically deactivated factors scaffold the assembly while the exit tunnel is blocked. Together, this extensive network of accessory factors stabilizes the immature sites and connects the functionally important regions of the mitoribosomal large subunit.
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| 35. |
- Tobiasson, Victor, 1994-
(författare)
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On the Origin and Evolution of the Mitochondrial Ribosome
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The ribosome is among the most ancient, intricate and well studied macromolecular complexes in biology. Predating the earliest divergence of life, its core molecular structure has remained mostly unchanged for more than three billion years. In stark contrast to its monolithic ancestor, the mitochondrial ribosome represents one of the most architecturally diverse protein complexes investigated. This work is an attempt at reconciling these two paradigms. In this thesis I first briefly cover the evolutionary history of the mitochondrial ribosome: from its ancient origins, through the process of Eukaryogenesis and the development of mitochondria, to its current state. Following this I present a comprehensive and integrated comparative analysis of the current mitoribosomal structures. Using these structural observations as a starting point I then summarise the current knowledge regarding the evolutionary trends of mitochondrial ribosomes. Finally I review and discuss potential genetic mechanisms and evolutionary pressures which could have produced such a vibrant diversity of structures. Together with this analysis I present monosome structures from the ciliate Tetrahymena thermophila and chlorophycean Polytomella magna together with an assembly intermediate of the large subunit from Trypanosoma brucei. Together, I hope to demonstrate the impact of the unique mitochondrial environment on the evolution of the mitochondrial ribosome.
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| 36. |
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| 37. |
- Tobiasson, Victor, et al.
(författare)
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Structure of a mitochondrial ribosome with fragmented rRNA in complex with membrane-targeting elements
- 2022
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Mitoribosomes of green algae display a great structural divergence from their tracheophyte relatives, with fragmentation of both rRNA and proteins as a defining feature. Here, we report a 2.9 angstrom resolution structure of the mitoribosome from the alga Polytomella magna harbouring a reduced rRNA split into 13 fragments. We found that the rRNA contains a non-canonical reduced form of the 5S, as well as a permutation of the LSU domain I. The mt-5S rRNA is stabilised by mL40 that is also found in mitoribosomes lacking the 5S, which suggests an evolutionary pathway. Through comparison to other ribosomes with fragmented rRNAs, we observe that the pattern is shared across large evolutionary distances, and between cellular compartments, indicating an evolutionary convergence and supporting the concept of a primordial fragmented ribosome. On the protein level, eleven peripherally associated HEAT-repeat proteins are involved in the binding of 3' rRNA termini, and the structure features a prominent pseudo-trimer of one of them (mL116). Finally, in the exit tunnel, mL128 constricts the tunnel width of the vestibular area, and mL105, a homolog of a membrane targeting component mediates contacts with an inner membrane bound insertase. Together, the structural analysis provides insight into the evolution of the ribosomal machinery in mitochondria.
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| 38. |
- Tobiasson, Victor, et al.
(författare)
-
Structure of a mitochondrial ribosome with fragmented rRNA in complexwith membrane-targeting elements
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Mitoibosomes of green alga belong to a diverged type with extreme fragmentation in rRNA andprotein material. We present a 2.9-Å resolution structure of an algal mitoribosome with reducedrRNA that is split in to 13 fragments. The architecture features a fragmentation pattern that hassimilarities with apicomplexan parasites. The unique phenomena of the rRNA include permutationand incorporation of a non-canonical and reduced mt-5S rRNA. On the protein level, elevenperipherally associated HEAT-repeat proteins involved in rRNA binding, and a specific trimer ofmL116 binds 3’ termini of three rRNA fragments. In the exit tunnel, mL128 constricts the path,and mL105 a homolog of a membrane targeting component mediates contacts with an innermembrane-bound insertase. Although overall protein content at the tunnel exit site of themitoribosome varies among eukaryotes, we find that the mechanisms of the constriction andmembrane tethering are shared between the algal and mammalian lineages. Therefore, our datareveals characteristics of fragmented rRNA an unexpected convergent evolution in the regulationof protein synthesis in mitochondria.
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| 39. |
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| 40. |
- Wú, Fēi, 1993-, et al.
(författare)
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Structure of the II2-III2-IV2 mitochondrial supercomplex from the parasite Perkinsus marinus
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Respiratory complexes have co-evolved into supercomplexes in different clades to sustain energy production at the basis of eukaryotic life. In this study, using cryogenic electron microscopy, we determined the 2.1 Å resolution structure of a 104-subunit II2-III2-IV2 supercomplex from the parasite Perkinsus marinus, related to Apicomplexa, capable of complete electron transport from succinate to molecular oxygen. A feature of the parasite is the association of two copies of complex II via the apicomplexan subunit SDHG that interacts with both complexes III and IV and bridge the supercomplex. In the c1 state, we identified two protein factors, ISPR1 and ISPR2 bound on the surface of complex III, where Cytochrome c docks, acting as negative regulators. The acquisition of 15 specific subunits to complex IV results in its lateral offset, increasing the distance between the Cytochrome c electron donor and acceptor sites. The domain homologous to canonical mitochondria-encoded transmembrane subunit COX2 is made of three separate polypeptides encoded in the nucleus, and their correct assembly is a prerequisite for electron transport in the supercomplex. Subunits Cytochrome b and COX1 comprise a +2 frameshift introduced during protein synthesis by the mitoribosome. Among 114 modelled endogenous lipids, we detect a direct contribution to the formation of the divergent supercomplex and its functional sites, including assembly of CII and ubiquinone binding. Together, our findings expose the uniqueness of the principal components of bioenergetics in the mitochondria of parasites.
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