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  • 1. Delguste, Martin
    et al.
    Peerboom, Nadia
    Le Brun, Gregoire
    Trybala, Edward
    Olofsson, Sigvard
    Bergström, Tomas
    Alsteens, David
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Regulatory Mechanisms of the Mucin-Like Region on Herpes Simplex Virus during Cellular Attachment2019In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, no 3, p. 534-542Article in journal (Refereed)
    Abstract [en]

    Mucin-like regions, characterized by a local high density of O-linked glycosylation, are found on the viral envelope glycoproteins of many viruses. Herpes simplex virus type 1 (HSV-1), for example, exhibits a mucin-like region on its glycoprotein gC, a viral protein involved in initial recruitment of the virus to the cell surface via interaction with sulfated glycosaminoglycans. So far, this mucin-like region has been proposed to play a key role in modulating the interactions with cellular glycosaminoglycans, and in particular to promote release of HSV-1 virions from infected cells. However, the molecular mechanisms and the role as a pathogenicity factor remains unclear. Using single virus particle tracking, we show that the mobility of chondroitin sulfate-bound HSV-1 virions is decreased in absence of the mucin-like region. This decrease in mobility correlates with an increase in HSV-1-chondroitin sulfate binding forces as observed using atomic force microscopy-based force spectroscopy. Our data suggest that the mucin-like region modulates virus-glycosaminoglycan interactions by regulating the affinity, type, and number of glycoproteins involved in the virus glycosaminoglycan interaction. This study therefore presents new evidence for a role of the mucin-like region in balancing the interaction of HSV-1 with glycosaminoglycans and provides further insights into the molecular mechanisms used by the virus to ensure both successful cell entry and release from the infected cell.

  • 2.
    Hedberg, Christian
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Dortmund, Germany.
    Itzen, Aymelt
    Center for Integrated Protein Science Munich, Chemistry Department, Technische Universität München, Garching, Germany.
    Molecular perspectives on protein adenylylation2015In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 10, no 1, p. 12-21Article, review/survey (Refereed)
    Abstract [en]

    In the cell, proteins are frequently modified covalently at specific amino acids with post-translational modifications, leading to a diversification of protein functions and activities. Since the introduction of high-resolution mass spectrometry, new post-translational modifications are constantly being discovered. One particular modification is the adenylylation of mammalian proteins. In adenylylation, adenosine triphosphate (ATP) is utilized to attach an adenosine monophosphate at protein threonine or tyrosine residues via a phosphodiester linkage. Adenylylation is particularly interesting in the context of infections by bacterial pathogens during which mammalian proteins are manipulated through AMP attachment via secreted bacterial factors. In this review, we summarize the role and regulation of enzymatic adenylylation and the mechanisms of catalysis. We also refer to recent methods for the detection of adenylylated proteins by modification-specific antibodies, ATP analogues equipped with chemical handles, and mass spectrometry approaches. Additionally, we review screening approaches for inhibiting adenylylation and briefly discuss related modifications such as phosphocholination and phosphorylation.

  • 3. Kuru, Erkin
    et al.
    Radkov, Atanas
    Meng, Xin
    Egan, Alexander
    Alvarez, Laura
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dowson, Amanda
    Booher, Garrett
    Breukink, Eefjan
    Roper, David I.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Vollmer, Waldemar
    Brun, Yves
    VanNieuwenhze, Michael S.
    Mechanisms of Incorporation for D-Amino Acid Probes That Target Peptidoglycan Biosynthesis2019In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, no 12, p. 2745-2756Article in journal (Refereed)
    Abstract [en]

    Bacteria exhibit a myriad of different morphologies, through the synthesis and modification of their essential peptidoglycan (PG) cell wall. Our discovery of a fluorescent D-amino acid (FDAA)-based PG labeling approach provided a powerful method for observing how these morphological changes occur. Given that PG is unique to bacterial cells and a common target for antibiotics, understanding the precise mechanism(s) for incorporation of (F)DAA-based probes is a crucial determinant in understanding the role of PG synthesis in bacterial cell biology and could provide a valuable tool in the development of new antimicrobials to treat drug-resistant antibacterial infections. Here, we systematically investigate the mechanisms of FDAA probe incorporation into PG using two model organisms Escherichia coli (Gram-negative) and Bacillus subtilis (Gram-positive). Our in vitro and in vivo data unequivocally demonstrate that these bacteria incorporate FDAAs using two extracytoplasmic pathways: through activity of their D,D-transpeptidases, and, if present, by their L,D-transpeptidases and not via cytoplasmic incorporation into a D-Ala-D-Ala dipeptide precursor. Our data also revealed the unprecedented finding that the DAA-drug, D-cycloserine, can be incorporated into peptide stems by each of these transpeptidases, in addition to its known inhibitory activity against D-alanine racemase and D-Ala-D-Ala ligase. These mechanistic findings enabled development of a new, FDAA-based, in vitro labeling approach that reports on subcellular distribution of muropeptides, an especially important attribute to enable the study of bacteria with poorly defined growth modes. An improved understanding of the incorporation mechanisms utilized by DAA-based probes is essential when interpreting results from high resolution experiments and highlights the antimicrobial potential of synthetic DAAs.

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  • 4.
    Lindgren, Anders E. G.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Karlberg, Tobias
    Thorsell, Ann-Gerd
    Hesse, Mareike
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekblad, Torun
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pinto, Ana Filipa
    Weigelt, Johan
    Hottiger, Michael O.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schueler, Herwig
    PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP32013In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 8, no 8, p. 1698-1703Article in journal (Refereed)
    Abstract [en]

    Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12, members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.

  • 5.
    Pansieri, Jonathan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ostojic, Lucija
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Iashchishyn, Igor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Magzoub, Mazin
    Wallin, Cecilia
    Warmlander, Sebastian K. T. S.
    Graslund, Astrid
    Ngoc, Mai Nguyen
    Smirnovas, Vytautas
    Svedruzic, Zeljko
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs2019In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, no 7, p. 1410-1417Article in journal (Refereed)
    Abstract [en]

    Amyloid cascade and neuroinflammation are hallmarks of neurodegenerative diseases, and pro-inflammatory S100A9 protein is central to both of them. Here, we have shown that NCAM1 peptide constructs carrying polycationic sequences derived from A beta peptide (KKLVFF) and PrP protein (KKRPKP) significantly promote the S100A9 amyloid self-assembly in a concentration-dependent manner by making transient interactions with individual S100A9 molecules, perturbing its native structure and acting as catalysts. Since the individual molecule misfolding is a rate-limiting step in S100A9 amyloid aggregation, the effects of the NCAM1 construct on the native S100A9 are so critical for its amyloid self-assembly. S100A9 rapid self assembly into large aggregated clumps may prevent its amyloid tissue propagation, and by modulating S100A9 aggregation as a part of the amyloid cascade, the whole process may be effectively tuned.

  • 6. Siegrist, M Sloan
    et al.
    Whiteside, Sarah
    Jewett, John C
    Aditham, Arjun
    Cava, Felipe
    Centro de Biologia Molecular Severo Ochoa, Universidad Autonoma de Madrid, Madrid, Spain.
    Bertozzi, Carolyn R
    (D)-amino acid chemical reporters reveal peptidoglycan dynamics of an intracellular pathogen2013In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 8, no 3, p. 500-505Article in journal (Refereed)
    Abstract [en]

    Peptidoglycan (PG) is an essential component of the bacterial cell wall. Although experiments with organisms in vitro have yielded a wealth of information on PG synthesis and maturation, it is unclear how these studies translate to bacteria replicating within host cells. We report a chemical approach for probing PG in vivo via metabolic labeling and bioorthogonal chemistry. A wide variety of bacterial species incorporated azide and alkyne-functionalized d-alanine into their cell walls, which we visualized by covalent reaction with click chemistry probes. The d-alanine analogues were specifically incorporated into nascent PG of the intracellular pathogen Listeria monocytogenes both in vitro and during macrophage infection. Metabolic incorporation of d-alanine derivatives and click chemistry detection constitute a facile, modular platform that facilitates unprecedented spatial and temporal resolution of PG dynamics in vivo.

  • 7. Wu, Xuanjun
    et al.
    McKay, Craig
    Pett, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Leibniz-Institut für Analytische Wissenschaften ISAS e.V., Dortmund, Germany.
    Yu, Jin
    Schorlemer, Manuel
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Leibniz-Institut für Analytische Wissenschaften ISAS e.V., Dortmund, Germany.
    Ramadan, Sherif
    Lang, Shuyao
    Behren, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Leibniz-Institut für Analytische Wissenschaften ISAS e.V., Dortmund, Germany.
    Westerlind, Ulrika
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Leibniz-Institut für Analytische Wissenschaften ISAS e.V., Dortmund, Germany.
    Finn, M. G.
    Huang, Xuefei
    Synthesis and Immunological Evaluation of Disaccharide Bearing MUC-1 Glycopeptide Conjugates with Virus-like Particles2019In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, no 10, p. 2176-2184Article in journal (Refereed)
    Abstract [en]

    Mucin-1 (MUC1) is a highly attractive antigenic target for anticancer vaccines. Naturally existing MUC1 can contain multiple types of O-linked glycans, including the Thomsen–Friedenreich (Tf) antigen and the Sialyl Thomsen-nouveau (STn) antigen. In order to target these antigens as potential anticancer vaccines, MUC1 glycopeptides SAPDT*RPAP (T* is the glycosylation site) bearing the Tf and the STn antigen, respectively, have been synthesized. The bacteriophage Qβ carrier is a powerful carrier for antigen delivery. The conjugates of MUC1-Tf and -STn glycopeptides with Qβ were utilized to immunize immune-tolerant human MUC1 transgenic (MUC1.Tg) mice, which elicited superior levels of anti-MUC1 IgG antibodies with titers reaching over 2 million units. The IgG antibodies recognized a wide range of MUC1 glycopeptides bearing diverse glycans. Antibodies induced by Qβ-MUC1-Tf showed strongest binding, with MUC1-expressing melanoma B16-MUC1 cells, and effectively killed these cells in vitro. Vaccination with Qβ-MUC1-Tf first followed by tumor challenge in a lung metastasis model showed significant reductions of the number of tumor foci in the lungs of immunized mice as compared to those in control mice. This was the first time that a MUC1-Tf-based vaccine has shown in vivo efficacy in a tumor model. As such, Qβ-MUC1 glycopeptide conjugates have great potential as anticancer vaccines.

  • 8. Yin, Zhaojun
    et al.
    Wu, Xuanjun
    Kaczanowska, Katarzyna
    Sungsuwan, Suttipun
    Comellas Aragones, Marta
    Pett, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Yu, Jin
    Baniel, Claire
    Ulrika, Westerlind
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Finn, M. G.
    Huang, Xuefei
    Antitumor Humoral and T Cell Responses by Mucin-1 Conjugates of Bacteriophage Qβ in Wild-type Mice2018In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 13, no 6, p. 1668-1676Article in journal (Refereed)
    Abstract [en]

    Mucin-1 (MUC1) is one of the top ranked tumor associated antigens. In order to generate effective anti-MUC1 immune responses as potential anticancer vaccines, MUC1 peptides and glycopeptides have been covalently conjugated to bacteriophage Qβ. Immunization of mice with these constructs led to highly potent antibody responses with IgG titers over one million, which are among the highest anti-MUC1 IgG titers reported to date. Furthermore, the high IgG antibody levels persisted for more than six months. The constructs also elicited MUC1 specific cytotoxic T cells, which can selectively kill MUC1 positive tumor cells. The unique abilities of Qβ-MUC1 conjugates to powerfully induce both antibody and cytotoxic T cell immunity targeting tumor cells bode well for future translation of the constructs as anticancer vaccines.

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