CIISB Research Highlights Archive

  • Nature Communications 2023 - 2

    Nature Communications 2023 - 2

    Micro-CT images of P0 pups with control and low iron diet, containing 178.58 mg iron/kg or 5.16 mg iron/kg, respectively. The kidney (red), interscapular brown adipose tissue (IBAT) (yellow), liver (green), and adrenal glands (orange) are segmented using 3D Visualization software and superimposed onto the pups.

    Julian Petersen and Igor Adamyeko Research Group

    Significance

    In this study, we use comparative genomics to uncover a gene with uncharacterized function (1700011H14Rik/C14orf105/CCDC198), which we hereby name FAME (Factor Associated with Metabolism and Energy). We observe that FAME shows an unusually high evolutionary divergence in birds and mammals. Through the comparison of single nucleotide polymorphisms, we identify gene flow of FAME from Neandertals into modern humans. We conduct knockout experiments on animals and observe altered body weight and decreased energy expenditure in Fame knockout animals, corresponding to genome-wide association studies linking FAME with higher body mass index in humans. Gene expression and subcellular localization analyses reveal that FAME is a membrane-bound protein enriched in the kidneys. Although the gene knockout results in structurally normal kidneys, we detect higher albumin in urine and lowered ferritin in the blood. Through experimental validation, we confirm interactions between FAME and ferritin and show co-localization in vesicular and plasma membranes.

    Petersen, J., Englmaier, L., Artemov, A.V. et al. A previously uncharacterized Factor Associated with Metabolism and Energy (FAME/C14orf105/CCDC198/1700011H14Rik) is related to evolutionary adaptation, energy balance, and kidney physiology.

    Nat Commun. 14, 3092 (2023). https://doi.org/10.1038/s41467-023-38663-7

     

  • Nature Plants 2023

    Nature Plants 2023

    a, The view of the C2S2 supercomplex from the lumenal side with indicated subunits of light-harvesting antenna, Lhcb5, Lhcb8 and the S-LHCII trimer, bound to the dimeric core complex. b, The side view of the C2S2 supercomplex along the membrane plane. c, Assigned subunits of the core complex.

    Roman Kouřil Research Group

    Significance

    The heart of oxygenic photosynthesis is the water-splitting photosystem II (PSII), which forms supercomplexes with a variable amount of peripheral trimeric light-harvesting complexes (LHCII). Our knowledge of the structure of green plant PSII supercomplex is based on findings obtained from several representatives of green algae and flowering plants; however, data from a non-flowering plant are currently missing. Here we report a cryo-electron microscopy structure of PSII supercomplex from spruce, a representative of non-flowering land plants, at 2.8 Å resolution. Compared with flowering plants, PSII supercomplex in spruce contains an additional Ycf12 subunit, Lhcb4 protein is replaced by Lhcb8, and trimeric LHCII is present as a homotrimer of Lhcb1. Unexpectedly, we have found α-tocopherol (α-Toc)/α-tocopherolquinone (α-TQ) at the boundary between the LHCII trimer and the inner antenna CP43. The molecule of α-Toc/α-TQ is located close to chlorophyll a614 of one of the Lhcb1 proteins and its chromanol/quinone head is exposed to the thylakoid lumen. The position of α-Toc in PSII supercomplex makes it an ideal candidate for the sensor of excessive light, as α-Toc can be oxidized to α-TQ by high-light-induced singlet oxygen at low lumenal pH. The molecule of α-TQ appears to shift slightly into the PSII supercomplex, which could trigger important structure–functional modifications in PSII supercomplex. Inspection of the previously reported cryo-electron microscopy maps of PSII supercomplexes indicates that α-Toc/α-TQ can be present at the same site also in PSII supercomplexes from flowering plants, but its identification in the previous studies has been hindered by insufficient resolution.

    Opatíková, M., Semchonok, D.A., Kopečný, D. et al. Cryo-EM structure of a plant photosystem II supercomplex with light-harvesting protein Lhcb8 and α-tocopherol.

    Nat. Plants 9, 1359–1369 (2023). https://doi.org/10.1038/s41477-023-01483-0

  • Nature Structural and Molecular Biology 2023

    Nature Structural and Molecular Biology 2023

    The central ring shows a superimposition of the binding sites on the SSU (gray) of the antibiotics tetracycline (blue), spectinomycin (yellow), hygromycin B (pink), kasugamycin (red), apramycin (green), gentamicin (cyan) and streptomycin (orange), which is surrounded by insets highlighting the interactions between the drug and the 16S rRNA (gray), waters (red spheres with gray transparent density), magnesium ions (green spheres), putative K+ ions (purple sphere with transparent gray density) and uS12 (orange). Potential hydrogen bonds are indicated as dashed lines, colored orange for direct interaction between the drug and the small subunit, cyan for water-mediated interactions, green for Mg2+ ion coordination and purple for K+ coordination.

    Daniel Wilson Research Group

    Significance

    The ribosome is a major target for clinically used antibiotics, but multidrug resistant pathogenic bacteria are making our current arsenal of antimicrobials obsolete. Here we present cryo-electron-microscopy structures of 17 distinct compounds from six different antibiotic classes bound to the bacterial ribosome at resolutions ranging from 1.6 to 2.2 Å. The improved resolution enables a precise description of antibiotic–ribosome interactions, encompassing solvent networks that mediate multiple additional interactions between the drugs and their target. Our results reveal a high structural conservation in the binding mode between antibiotics with the same scaffold, including ordered water molecules. Water molecules are visualized within the antibiotic binding sites that are preordered, become ordered in the presence of the drug and that are physically displaced on drug binding. Insight into RNA–ligand interactions will facilitate development of new antimicrobial agents, as well as other RNA-targeting therapies.

    Paternoga, H., Crowe-McAuliffe, C., Bock, L.V. et al. Structural conservation of antibiotic interaction with ribosomes.

    Nat Struct Mol Biol (2023). https://doi.org/10.1038/s41594-023-01047-y

  • Nature Communications 2023

    Nature Communications 2023

    Cryo-EM density maps showing side views of ISG65:C3 (left), and ISG65:C3b (right) at two different angles. ISG65 is represented by map regions coloured in green. Interacting domains in C3 and C3b are depicted in blue. In both C3 conformations, TED provides the primary interface. ISG65 and TED show a high degree of shape complementarity. Smaller, secondary interfaces are located in ANA (native C3) and CUB (C3b). The remaining scaffold (C3c, grey) shows no additional contact points.

    Sebastian Zoll Research Group

    Significance

    African Trypanosomes have developed elaborate mechanisms to escape the adaptive immune response, but little is known about complement evasion particularly at the early stage of infection. Here we show that ISG65 of the human-infective parasite Trypanosoma brucei gambiense is a receptor for human complement factor C3 and its activation fragments and that it takes over a role in selective inhibition of the alternative pathway C5 convertase and thus abrogation of the terminal pathway. No deposition of C4b, as part of the classical and lectin pathway convertases, was detected on trypanosomes. We present the cryo-electron microscopy (EM) structures of native C3 and C3b in complex with ISG65 which reveal a set of modes of complement interaction. Based on these findings, we propose a model for receptor-ligand interactions as they occur at the plasma membrane of blood-stage trypanosomes and may facilitate innate immune escape of the parasite.

    Sülzen, H., Began, J., Dhillon, A. et al. Cryo-EM structures of Trypanosoma brucei gambiense ISG65 with human complement C3 and C3b and their roles in alternative pathway restriction.

    Nat Commun 14, 2403 (2023). https://doi.org/10.1038/s41467-023-37988-7

  • Small 2023

    Small 2023

    General outline of the phototrapping and photofragmentation of microplastics in aqueous media using superstructured TiO2 microrobots.

    Martin Pumera Research Group

    Significance

    Microplastics, which comprise one of the omnipresent threats to human health, are diverse in shape and composition. Their negative impacts on human and ecosystem health provide ample incentive to design and execute strategies to trap and degrade diversely structured microplastics, especially from water. This work demonstrates the fabrication of single-component TiO2 superstructured microrobots to photo-trap and photo-fragment microplastics. In a single reaction, rod-like microrobots diverse in shape and with multiple trapping sites, are fabricated to exploit the asymmetry of the microrobotic system advantageous for propulsion. The microrobots work synergistically to photo-catalytically trap and fragment microplastics in water in a coordinated fashion. Hence, a microrobotic model of “unity in diversity” is demonstrated here for the phototrapping and photofragmentation of microplastics. During light irradiation and subsequent photocatalysis, the surface morphology of microrobots transformed into porous flower-like networks that trap microplastics for subsequent degradation. This reconfigurable microrobotic technology represents a significant step forward in the efforts to degrade microplastics.

    Sanjay Gopal Ullattil and Martin Pumera: Light-Powered Self-Adaptive Mesostructured Microrobots for Simultaneous Microplastics Trapping and Fragmentation via in situ Surface Morphing.

    Small 2023, 2301467, https://doi.org/10.1002/smll.202301467

     

  • Molecular Neurodegeneration 2023

    Molecular Neurodegeneration 2023

    Comparison of V-shaped packing in ApoE4 and ApoE3 structures. The conformational change of the loop connecting helices H2 and H3 in ApoE3 structures (PDB IDs: 1OR2 and 1OR3) leads to V-shaped packing but to a different residue arrangement at the self-association interface than in ApoE4 structures.

    Martin Marek Research Group

    Significance

    Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer’s Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown. Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level. We found that C112R substitution in ApoE4 induces long-distance (> 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol. Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.

    Nemergut, M., Marques, S.M., Uhrik, L. et al.: Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate.

    Mol. Neurodegeneration 2023, 18, 38 (2023). https://doi.org/10.1186/s13024-023-00620-9

     

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