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Sökning: WFRF:(Thygesen K) > Naturvetenskap

  • Resultat 1-4 av 4
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1.
  • Clabbers, Max T. B., et al. (författare)
  • MyD88 TIR domain higher-order assembly interactions revealed by microcrystal electron diffraction and serial femtosecond crystallography
  • 2021
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • MyD88 and MAL are Toll-like receptor (TLR) adaptors that signal to induce pro-inflammatory cytokine production. We previously observed that the TIR domain of MAL (MALTIR) forms filaments in vitro and induces formation of crystalline higher-order assemblies of the MyD88 TIR domain (MyD88TIR). These crystals are too small for conventional X-ray crystallography, but are ideally suited to structure determination by microcrystal electron diffraction (MicroED) and serial femtosecond crystallography (SFX). Here, we present MicroED and SFX structures of the MyD88TIR assembly, which reveal a two-stranded higher-order assembly arrangement of TIR domains analogous to that seen previously for MALTIR. We demonstrate via mutagenesis that the MyD88TIR assembly interfaces are critical for TLR4 signaling in vivo, and we show that MAL promotes unidirectional assembly of MyD88TIR. Collectively, our studies provide structural and mechanistic insight into TLR signal transduction and allow a direct comparison of the MicroED and SFX techniques.
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2.
  • Gersing, Sarah K., et al. (författare)
  • Mapping the degradation pathway of a disease-linked aspartoacylase variant
  • 2021
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Canavan disease is a severe progressive neurodegenerative disorder that is characterized by swelling and spongy degeneration of brain white matter. The disease is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene, including the substitution C152W. ASPA C152W is associated with greatly reduced protein levels in cells, yet biophysical experiments suggest a wild-type like thermal stability. Here, we use ASPA C152W as a model to investigate the degradation pathway of a disease-causing protein variant. When we expressed ASPA C152W in Saccharomyces cerevisiae, we found a decreased steady state compared to wild-type ASPA as a result of increased proteasomal degradation. However, molecular dynamics simulations of ASPA C152W did not substantially deviate from wild-type ASPA, indicating that the native state is structurally preserved. Instead, we suggest that the C152W substitution interferes with the de novo folding pathway resulting in increased proteasomal degradation before reaching its stable conformation. Systematic mapping of the protein quality control components acting on misfolded and aggregation-prone species of C152W, revealed that the degradation is highly dependent on the molecular chaperone Hsp70, its co-chaperone Hsp110 as well as several quality control E3 ubiquitin-protein ligases, including Ubr1. In addition, the disaggregase Hsp104 facilitated refolding of aggregated ASPA C152W, while Cdc48 mediated degradation of insoluble ASPA protein. In human cells, ASPA C152W displayed increased proteasomal turnover that was similarly dependent on Hsp70 and Hsp110. Our findings underscore the use of yeast to determine the protein quality control components involved in the degradation of human pathogenic variants in order to identify potential therapeutic targets. Author summary Canavan disease is a fatal neurodegenerative disorder which is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene. Although the molecular mechanism of most disease-causing substitutions remains to be examined, some variants have been suggested to cause the loss-of-function phenotype by perturbing the structural stability of ASPA. So far the cellular fate of these variants have not been examined. Here we examine the stability and degradation pathways of the disease-causing ASPA variant C152W. In yeast cells, ASPA C152W showed decreased steady-state protein levels as a result of increased proteasomal turnover. Our molecular dynamics simulations showed that the C152W substitution did not globally perturb the native structure of ASPA. Instead we propose that ASPA C152W is targeted by the protein quality control system during de novo folding. Specifically, we found that the molecular chaperone Hsp70, its co-chaperone Hsp110, and the E3 ubiquitin-protein ligase Ubr1 promote degradation of ASPA C152W. When we expressed ASPA C152W in cultured human cells, we found that Hsp70 and Hsp110 similarly mediated degradation. Therefore, we propose that Hsp110 should be further examined as a potential therapeutic target in Canavan disease and other protein misfolding diseases.
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3.
  • Fischer, M., et al. (författare)
  • Controlled generation of luminescent centers in hexagonal boron nitride by irradiation engineering
  • 2021
  • Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Luminescent centers in the two-dimensional material hexagonal boron nitride have the potential to enable quantum applications at room temperature. To be used for applications, it is crucial to generate these centers in a controlled manner and to identify their microscopic nature. Here, we present a method inspired by irradiation engineering with oxygen atoms. We systematically explore the influence of the kinetic energy and the irradiation fluence on the generation of luminescent centers. We find modifications of their density for both parameters, while a fivefold enhancement is observed with increasing fluence. Molecular dynamics simulations clarify the generation mechanism of these centers and their microscopic nature. We infer that VNCB and V-B are the most likely centers formed. Ab initio calculations of their optical properties show excellent agreement with our experiments. Our methodology generates quantum emitters in a controlled manner and provides insights into their microscopic nature.
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4.
  • Hao, Xian, et al. (författare)
  • Direct measurement and modulation of single-molecule coordinative bonding forces in a transition metal complex
  • 2013
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • Coordination chemistry has been a consistently active branch of chemistry since Werner’s seminal theory of coordination compounds inaugurated in 1893, with the central focus on transition metal complexes. However, control and measurement of metal–ligand interactions at the single-molecule level remain a daunting challenge. Here we demonstrate an interdisciplinary and systematic approach that enables measurement and modulation of the coordinative bonding forces in a transition metal complex. Terpyridine is derived with a thiol linker, facilitating covalent attachment of this ligand on both gold substrate surfaces and gold-coated atomic force microscopy tips. The coordination and bond breaking between terpyridine and osmium are followed in situ by electrochemically controlled atomic force microscopy at the single-molecule level. The redox state of the central metal atom is found to have a significant impact on the metal–ligand interactions. The present approach represents a major advancement in unravelling the nature of metal–ligand interactions and could have broad implications in coordination chemistry.
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  • Resultat 1-4 av 4

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