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- Carlesso, Antonio, 1990, et al.
(författare)
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New insights on human IRE1 tetramer structures based on molecular modeling
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Inositol-Requiring Enzyme 1 alpha (IRE1 alpha; hereafter IRE1) is a transmembrane kinase/ribonuclease protein related with the unfolded protein response (UPR) signaling. Experimental evidence suggests that IRE1 forms several three dimensional (3D) structural variants: dimers, tetramers and higher order oligomers, where each structural variant can contain different IRE1 conformers in different arrangements. For example, studies have shown that two sets of IRE1 dimers exist; a face-to-face dimer and a back-to-back dimer, with the latter considered the important unit for UPR signaling propagation. However, the structural configuration and mechanistic details of the biologically important IRE1 tetramers are limited. Here, we combine protein-protein docking with molecular dynamics simulations to derive human IRE1 tetramer models and identify a molecular mechanism of IRE1 activation. To validate the derived models of the human IRE1 tetramer, we compare the dynamic behavior of the models with the yeast IRE1 tetramer crystallographic structure. We show that IRE1 tetramer conformational changes could be linked to the initiation of the unconventional splicing of mRNA encoding X-box binding protein-1 (XBP1), which allows for the expression of the transcription factor XBP1s (XBP1 spliced). The derived IRE1 tetrameric models bring new mechanistic insights about the IRE1 molecular activation mechanism by describing the IRE1 tetramers as active protagonists accommodating the XBP1 substrate.
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- Hörberg, Johanna, et al.
(författare)
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Specifically bound BZIP transcription factors modulate DNA supercoiling transitions
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Torsional stress on DNA, introduced by molecular motors, constitutes an important regulatory mechanism of transcriptional control. Torsional stress can modulate specific binding of transcription factors to DNA and introduce local conformational changes that facilitate the opening of promoters and nucleosome remodelling. Using all-atom microsecond scale molecular dynamics simulations together with a torsional restraint that controls the total twist of a DNA fragment, we address the impact of torsional stress on DNA complexation with a human BZIP transcription factor, MafB. We gradually over- and underwind DNA alone and in complex with MafB by 0.5 degrees per dinucleotide step, starting from the relaxed state to a maximum of 5 degrees per dinucleotide step, monitoring the evolution of the protein-DNA contacts at different degrees of torsional strain. Our computations show that MafB changes the DNA sequence-specific response to torsional stress. The dinucleotide steps that are susceptible to absorbing most of the torsional stress become more torsionally rigid, as they are involved in protein-DNA contacts. Also, the protein undergoes substantial conformational changes to follow the stress-induced DNA deformation, but mostly maintains the specific contacts with DNA. This results in a significant asymmetric increase of free energy of DNA twisting transitions, relative to free DNA, where overtwisting is more energetically unfavourable. Our data suggest that specifically bound BZIP factors could act as torsional stress insulators, modulating the propagation of torsional stress along the chromatin fibre, which might promote cooperative binding of collaborative DNA-binding factors.
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- Hörberg, Ulrica, 1968-, et al.
(författare)
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Women's lived experience of well-being in everyday life when living with a stress-related illness
- 2020
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Ingår i: International Journal of Qualitative Studies on Health and Well-being. - : Informa UK Limited. - 1748-2623 .- 1748-2631. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The aim of the study was to describe how women with stress-related illness experience well-being in everyday life. Methods: The study was based on a reflective lifeworld research (RLR) approach and the methodological principles of openness, flexibility and bridling. Twelve women, aged 27-54 years, diagnosed with stress-related illness were included. Data were collected with lifeworld interviews based on photographs taken by the women relating to well-being in everyday life. The data were analysed for meaning. Results: Well-being emerged in situations where women could feel an unconditional beingness. This entails not having demands on oneself and includes some form of freedom from having to perform. The surroundings and supportive environments are important for this unconditional beingness to be present. In order to feel well-being in everyday life, the women need to balance their energy and find helpful tools that can achieve a balance in everyday life. Conclusions: Healthcare staff need to understand the importance of unconditional beingness in supportive environments for patients living with stress-related illness in order to support their health and well-being. It is also important to support patients in finding helpful tools that can aid them to achieve a balance in everyday life.
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