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  • 1. Elmlund, Hans
    et al.
    Baraznenok, Vera
    Linder, Tomas
    Szilagyi, Zsolt
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hebert, Hans
    Lindahl, Martin
    Gustafsson, Claes M
    Cryo-EM reveals promoter DNA binding and conformational flexibility of the general transcription factor TFIID2009In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 17, no 11, p. 1442-1452Article in journal (Refereed)
    Abstract [en]

    The general transcription factor IID (TFIID) is required for initiation of RNA polymerase II-dependent transcription at many eukaryotic promoters. TFIID comprises the TATA-binding protein (TBP) and several conserved TBP-associated factors (TAFs). Recognition of the core promoter by TFIID assists assembly of the preinitiation complex. Using cryo-electron microscopy in combination with methods for ab initio single-particle reconstruction and heterogeneity analysis, we have produced density maps of two conformational states of Schizosaccharomyces pombe TFIID, containing and lacking TBP. We report that TBP-binding is coupled to a massive histone-fold domain rearrangement. Moreover, docking of the TBP-TAF1(N-terminus) atomic structure to the TFIID map and reconstruction of a TAF-promoter DNA complex helps to account for TAF-dependent regulation of promoter-TBP and promoter-TAF interactions.

  • 2.
    Forsgren, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Nordin, Frida
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Danielsson, Jens
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    A Novel mutation D96Mfs*8 in SOD1 identified in a Swedish ALS patient results in a truncated and heavily aggregation-prone proteinManuscript (preprint) (Other (popular science, discussion, etc.))
  • 3.
    Hosseinzadeh, Ava
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vodnala, Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kötemann, A
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Urban, Constantin F.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Adenosine is a drugable negative regulator of neutrophil activity during Candida albicans infectionManuscript (preprint) (Other academic)
  • 4.
    Jonna, Venkateswara Rao
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Crona, Mikael
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundin, Daniel
    Johansson, Samuel
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sjöberg, Britt-Marie
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Diversity in Overall Activity Regulation of Ribonucleotide Reductase2015In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 28, p. 17339-17348Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to the corresponding deoxyribonucleotides, which are used as building blocks for DNA replication and repair. This process is tightly regulated via two allosteric sites, the specificity site (s-site) and the overall activity site (a-site). The a-site resides in an N-terminal ATP cone domain that binds dATP or ATP and functions as an on/off switch, whereas the composite s-site binds ATP, dATP, dTTP, or dGTP and determines which substrate to reduce. There are three classes of RNRs, and class I RNRs consist of different combinations of α and β subunits. In eukaryotic and Escherichia coli class I RNRs, dATP inhibits enzyme activity through the formation of inactive α6 and α4β4 complexes, respectively. Here we show that the Pseudomonas aeruginosa class I RNR has a duplicated ATP cone domain and represents a third mechanism of overall activity regulation. Each α polypeptide binds three dATP molecules, and the N-terminal ATP cone is critical for binding two of the dATPs because a truncated protein lacking this cone could only bind dATP to its s-site. ATP activates the enzyme solely by preventing dATP from binding. The dATP-induced inactive form is an α4 complex, which can interact with β2 to form a non-productive α4β2 complex. Other allosteric effectors induce a mixture of α2 and α4 forms, with the former being able to interact with β2 to form active α2β2 complexes. The unique features of the P. aeruginosa RNR are interesting both from evolutionary and drug discovery perspectives.

  • 5.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Berdynski, Mariusz
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Polish Academy of Sciences, Warsaw, Poland.
    Hjertkvist, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Glass, Jonathan D.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in ALS patients and their relatives2017In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, no 5-6, p. 457-463Article in journal (Refereed)
    Abstract [en]

    Objective: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations.Methods: Blood samples from 4072 individuals, ALS patients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed. Coding SOD1 sequences were analysed by Sanger sequencing, exon copy number variations by fragment length analysis and by TaqMan Assay.Results: Of the 44 SOD1 mutations found, 75% caused severe destabilisation of the mutant protein but in 25% it was physically stable. Mutations producing structural changes caused halved erythrocyte SOD1 activities. There were no differences in SOD1 activities between patients without a SOD1 mutation and control individuals or carriers of TBK1 mutations and C9orf72(HRE). In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Thalassemias and iron deficiency were associated with increased SOD1 activity/haemoglobin ratios.Conclusion: Adjunct erythrocyte SOD1 activity analysis reliably signals destabilising SOD1 mutations including intronic mutations that are missed by exon sequencing.

  • 6.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Berdynski, Mariusz
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hjertkvist, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Glass, Jonathan D.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in erythrocytes in ALS patients and their relativesManuscript (preprint) (Other academic)
    Abstract [en]

    Our objective was to in blood samples from 3723 individuals including ALS patients without a coding SOD1 mutation and 372 control individuals characterize stabilities of mutant SOD1s, compare SOD1 enzymatic activities between patients with different genetic causes of ALS, and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. Erythrocyte SOD1 enzymatic activities normalized to hemoglobin content were determined. Coding SOD1 sequences were analyzed by Sanger sequencing, copy number variations by fragment length analysis and by TaqMan Assay. Hemoglobin disorders were searched for. Of the 46 SOD1 mutations found, ¾ caused severe destabilization of the mutant protein but in ¼ SOD1 was essentially physically stable. Mutations producing structural changes all caused halved SOD activities. There were no differences in SOD1 activities between controls and patients without any detected SOD1 mutations or patients with C9ORF72HRE or TBK1 mutations. In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Also, no uncommon variants in exon-flanking sequences were detected. Thalassemias and iron deficiency anemia were associated with increased SOD1 activity/hemoglobin ratios. In conclusion, adjunct erythrocyte SOD activity analysis is of value to signal the presence of exon and splice-site-intron mutations that influence the SOD1 structure.

  • 7.
    Ranjbarian, Farahnaz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vodnala, Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vodnala, Sharvani Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Biochemistry, Institute of Biochemistry and Biophysics, Tehran University, Tehran, Iran.
    Thelander, Lars
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Trypanosoma brucei thymidine kinase is tandem protein consisting of two homologous parts, which together enable efficient substrate binding2012In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 21, p. 17628-17636Article in journal (Refereed)
    Abstract [en]

    Trypanosoma brucei causes African sleeping sickness, a disease for which existing chemotherapies are limited by their toxicity or lack of efficacy. We have found that four parasites, including T. brucei, contain genes where two or four thymidine kinase (TK) sequences are fused into a single open reading frame. The T. brucei full-length enzyme as well as its two constituent parts, domain 1 and domain 2, were separately expressed and characterized. Of potential interest for nucleoside analog development, T. brucei TK was less discriminative against purines than human TK1 with the following order of catalytic efficiencies: thymidine > deoxyuridine ≫ deoxyinosine > deoxyguanosine. Proteins from the TK1 family are generally dimers or tetramers, and the quaternary structure is linked to substrate affinity. T. brucei TK was primarily monomeric but can be considered a two-domain pseudodimer. Independent kinetic analysis of the two domains showed that only domain 2 was active. It had a similar turnover number (k(cat)) as the full-length enzyme but could not self-dimerize efficiently and had a 5-fold reduced thymidine/deoxyuridine affinity. Domain 1, which lacks three conserved active site residues, can therefore be considered a covalently attached structural partner that enhances substrate binding to domain 2. A consequence of the non-catalytic role of domain 1 is that its active site residues are released from evolutionary pressure, which can be advantageous for developing new catalytic functions. In addition, nearly identical 89-bp sequences present in both domains suggest that the exchange of genetic material between them can further promote evolution.

  • 8.
    Rofougaran, Reza
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Crona, Mikael
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Vodnala, Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sjöberg, Britt-Marie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Oligomerization status directs overall activity regulation of the Escherichia coli class Ia ribonucleotide reductase2008In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, no 51, p. 35310-35318Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductase (RNR) is a key enzyme for the synthesis of the four DNA building blocks. Class Ia RNRs contain two subunits, denoted R1 (α) and R2 (β). These enzymes are regulated via two nucleotide-binding allosteric sites on the R1 subunit, termed the specificity and overall activity sites. The specificity site binds ATP, dATP, dTTP, or dGTP and determines the substrate to be reduced, whereas the overall activity site binds dATP (inhibitor) or ATP. By using gas-phase electrophoretic mobility macromolecule analysis and enzyme assays, we found that the Escherichia coli class Ia RNR formed an inhibited α4β4 complex in the presence of dATP and an active α2β2 complex in the presence of ATP (main substrate: CDP), dTTP (substrate: GDP) or dGTP (substrate: ADP). The R1-R2 interaction was 30–50 times stronger in the α4β4 complex than in the α2β2complex, which was in equilibrium with free α2 and β2 subunits. Studies of a known E. coli R1 mutant (H59A) showed that deficient dATP inhibition correlated with reduced ability to form α4β4 complexes. ATP could also induce the formation of a generally inhibited α4β4 complex in the E. coli RNR but only when used in combination with high concentrations of the specificity site effectors, dTTP/dGTP. Both allosteric sites are therefore important for α4β4 formation and overall activity regulation. The E. coli RNR differs from the mammalian enzyme, which is stimulated by ATP also in combination with dGTP/dTTP and forms active and inactive α6β2 complexes.

  • 9.
    Wang, Chao
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Iashchishyn, Igor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Nyström, Sofie
    Klementieva, Oxana
    Kara, John
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bengtsson, Sara
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Foderà, Vito
    Vetri, Valeria
    Sancataldo, Giuseppe
    Horvath, Istvan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Moskalenko, Roman
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Pathology, Sumy State University, Sumy, Ukraine.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Gouras, Gunnar
    Marklund, Niklas
    Shankar, S.K.
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    S100A9-driven amyloid-neuroinflammatory cascade in traumatic brain injury as a risk factor for Alzheimer’s diseaseManuscript (preprint) (Other academic)
  • 10.
    Wang, Chao
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Iashchishyn, Igor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of General Chemistry, Sumy State University, Sumy, 40000, Ukraine.
    Pansieri, Jonathan
    Nyström, Sofie
    Klementieva, Oxana
    Kara, John
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Horvath, Istvan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Moskalenko, Roman
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Pathology, Sumy State University, Sumy, 40000, Ukraine.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gouras, Gunnar
    Kovacs, Gabor G.
    Shankar, S. K.
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer's Disease2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12836Article in journal (Refereed)
    Abstract [en]

    Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer's disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to A beta and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without A beta. S100A9 and A beta plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.

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