Gabriele Cordara

• Cordara, Gabriele; Bjerregaard-Andersen, Kaare & Krengel, Ute (2018). Virus-like immune defense protein in mushrooms. Structure.  ISSN 0969-2126.  26(3), s 369- 371 . doi: 10.1016/j.str.2018.02.013 Full text in Research Archive.
• Cordara, Gabriele; Manna, Dipankar & Krengel, Ute (2017). A family of papain-like fungal chimerolectins with distinct Ca2+-dependent activation mechanism. Biochemistry.  ISSN 0006-2960.  56(35), s 4689- 4700 . doi: 10.1021/acs.biochem.7b00317 Full text in Research Archive.
• Manna, Dipankar; Pust, Sascha; Torgersen, Maria Lyngaas; Cordara, Gabriele; Kunzler, Markus; Krengel, Ute & Sandvig, Kirsten (2017). Polyporus squamosus lectin 1a (PSL1a) exhibits cytotoxicity in mammalian cells by disruption of focal adhesions, inhibition of protein synthesis and induction of apoptosis. PLOS ONE.  ISSN 1932-6203.  12(1) . doi: 10.1371/journal.pone.0170716 Full text in Research Archive.
• Cordara, Gabriele; Van Eerde, Jan Hendrik; Grahn, Elin; Winter, HC; Goldstein, IJ & Krengel, Ute (2016). An unusual member of the papain superfamily: Mapping the catalytic cleft of the Marasmius oreades agglutinin (MOA) with a caspase inhibitor. PLOS ONE.  ISSN 1932-6203.  11(2) . doi: 10.1371/journal.pone.0149407 Full text in Research Archive.
• Cordara, Gabriele; Winter, Harry C.; Goldstein, Irwin J.; Krengel, Ute & Sandvig, Kirsten (2014). The fungal chimerolectin MOA inhibits protein and DNA synthesis in NIH/3T3 cells and may induce BAX-mediated apoptosis. Biochemical and Biophysical Research Communications - BBRC.  ISSN 0006-291X.  447(4), s 586- 589 . doi: 10.1016/j.bbrc.2014.04.043
• Cordara, Gabriele & Krengel, Ute (2012). Structure determination of lectins by x-ray crystallography - a hands-on approach, In A.P. Rauter & T.K. Lindhorst (ed.),  Carbohydrate Chemistry - Chemical and Biological Approaches.  Royal Society of Chemistry.  ISBN 9781849731546.  Volume 39.  s 222 - 246
• Cordara, Gabriele; Jacobsen, Wolfgang Mathias; Johansen, Harald Thidemann; Winter, Harry C.; Goldstein, IJ; Sandvig, Kirsten & Krengel, Ute (2011). Marasmius oreades agglutinin (MOA) is a chimerolectin with proteolytic activity. Biochemical and Biophysical Research Communications - BBRC.  ISSN 0006-291X.  408(3), s 405- 410 . doi: 10.1016/j.bbrc.2011.04.031

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• Manna, Dipankar; Cordara, Gabriele; Sandvig, Kirsten & Krengel, Ute (2016). I Robot- Biological nanomachines for fungal defense.
• Manna, Dipankar; Cordara, Gabriele; Pust, Sascha; Goldstein, Irwin J; Winter, Harry C.; Krengel, Ute & Sandvig, Kirsten (2015). PSL1a: a new member in the growing family of fungal chimerolectin.
• Manna, Dipankar; Cordara, Gabriele; Goldstein, Irwin J. & Krengel, Ute (2014). Conserved catalytic machinery in the MOA-PSL family of fungal chimerolectins.
• Manna, Dipankar; Cordara, Gabriele; Goldstein, Irwin J. & Krengel, Ute (2013). Towards structural and functional characterization of the Marasmius oreades agglutinin (MOA) and its role in host-pathogen interactions.
• Cordara, Gabriele (2013). Structure-function studies on the proteolytic mechanism of the Marasmius oreades agglutinin (MOA), a cytotoxic lectin.
• Cordara, Gabriele (2013). Thermofluor - A complementary technique in structural biology.
• Cordara, Gabriele; Krengel, Ute & Sandvig, Kirsten (2013). Structure-function studies on the Marasmius oreades agglutinin (MOA), a cytotoxic protease.
• Cordara, Gabriele; Goldstein, Irwin; Sandvig, Kirsten & Krengel, Ute (2012). Structure-function studies on the proteolytic activity of the Marasmius oreades agglutinin (MOA), a cytotoxic lectin. Show summary

  Lectins, sugar binding proteins of non-immune origin, are one of the many weapons used by plants and fungi to defend themselves against potential predators and parasites. This role is often fulfilled by the presence of an additional domain or subunit with catalytic function. The Marasmius oreades agglutinin (MOA) is a Gal-3Gal specific lectin extracted from the fruiting body of the Marasmius oreades mushroom. Parenterally administered MOA triggers a systemic effect in mice, which closely resembles the symptoms of the shiga toxin-induced hemolytic uremic syndrome (Stx-HUS) in humans. The structure of the MOA homodimer in complex with calcium, solved by X-ray crystallography [1], suggests an enzymatic function associated to the C-terminal dimerization domain, experimentally confirmed to be associated with proteolytic activity [2]. The enzymatically active domain of MOA shows an / hydrolase fold, bearing a structural resemblance to the enzymes of the papain-like cysteine peptidase family (clan CA). A notable feature in MOA is the conservation of two key residues of the catalytic triad (Cys215 and His257), while the third residue is substituted by an amino acid with similar properties (Glu274 in place of Asp). Here, we present further evidence, including crystallographic data, pointing to a key role of these residues for catalysis. [1] Grahn, E.M., Winter, H.C., Tateno, H., Goldstein, I.J., Krengel, U., (2009). J. Mol.. Biol., 390, 457–466 [2] Cordara, G., Egge-Jacobsen, W., Johansen, H.T., Winter, H.C., Goldstein, I.J., Sandvig, K., Krengel, U. (2011). Biochem. Biophys. Res. Commun., 408, 405-410.

• Cordara, Gabriele; Grahn, Elin; Jacobsen, Wolfgang Mathias; Goldstein, Irwin; Sandvig, Kirsten & Krengel, Ute (2012). Marasmius oreades Agglutinin (MOA): proteolytic activity of a cytotoxic lectin. Show summary

  Lectins, sugar binding proteins of non-immune origin, are one of the many weapons used by plants and fungi to defend themselves against potential predators and parasites. This role is often fulfilled by the presence of an additional domain or subunit with catalytic function. The Marasmius oreades agglutinin (MOA) is a Gal-α3Gal specific lectin extracted from the fruiting body of the Marasmius oreades mushroom. Parenterally administered MOA triggers a systemic effect in mice which closely resembles the symptoms of the shiga toxin-induced hemolytic uremic syndrome (Stx-HUS) in humans. The structure of MOA in complex calcium, recently solved by X-ray crystallography, elucidated the fine details of the sugar binding specificity of the N-terminal ricin B chain-like domain and showed the existence of a C-terminal domain with an α/β hydrolase fold. A search for structural homologues on the DALI database, using the coordinates of the C-terminal domain as the input, provided a significant number of top-ranking hits belonging to the family of the papain-like cysteine peptidases (clan CA). A notable feature is the conservation in MOA of two key residues of the catalytic triad (Cys215 and His257) while the third residue is substituted by an amino acid with similar properties (Glu274 in place of Asp), suggesting a potential hydrolytic activity associated to the C-terminal domain of MOA. Starting from this structure-based functional hypothesis, MOA was probed with a model substrate and found to be a calcium-dependent cysteine peptidase, with Cys215 acting as the catalytic residue.

• Munack, Steffi; Cordara, Gabriele; Van Eerde, Jan Hendrik; Kamarauskaite, Jurate; Roderer, Kathrin; Kast, Peter & Krengel, Ute (2012). Towards New Drugs Against Tuberculosis.
• Munack, Steffi; Roderer, Kathrin; Kamarauskaite, Jurate; Cordara, Gabriele; van Eerde, André; Kast, Peter & Krengel, Ute (2012). Towards New Drugs Against Tuberculosis.
• Cordara, Gabriele; Grahn, Elin; Jacobsen, Wolfgang Mathias; Goldstein, IJ; Sandvig, Kirsten & Krengel, Ute (2011). MOA : structure-driven discovery of the proteolytic activity of a cytotoxic lectin. Show summary

  Lectins, sugar binding proteins of non-immune origin, are one of the many weapons used by plants and fungi to defend themselves against potential predators and parasites. This role is often fulfilled by the presence of a domain with an additional function besides the sugar binding domain. The Marasmius oreades agglutinin (MOA) is a Gal-alpha3Gal specific lectin extracted from the fruiting body of the Marasmius oreades mushroom. Other than showing the rare ability to specifically agglutinate erythrocytes of the blood group B (containing the recognized disaccharide on the non-reducing end of the B glycotope), parenterally administered MOA triggers a systemic effect in mice which closely resembles the symptoms of the shiga toxin-induced hemolytic uremic syndrome (Stx-HUS) in humans. The structure of MOA in complex with the branched blood group B trisaccharide and calcium, recently solved by X-ray crystallography, elucidated the fine details of the sugar binding specificity of the N-terminal ricin B chain-like domain and showed the existence of an alpha/beta hydrolase fold C-terminal domain involved in dimerization A search for structural homologues, using the coordinates of the C-terminal domain as the input for the DALI database, provided a significant number of top-ranking hits belonging to the family of the papain-like cysteine peptidates (clan CA). A notable feature is the conservation in MOA of two key residues of the catalytic triad (Cys215 and His257) while the third residue is substituted by an amino acid with similar properties (Glu274 in place of Asp). Starting from the structure-based functional hypothesis of the presence of a hydrolytic activity associated to the C-terminal domain, MOA was probed with a model substrate and found to be a calcium-dependent cysteine peptidase, with Cys215 acting as the catalytic residue.

• Cordara, Gabriele; Grahn, Elin; Jacobsen, Wolfgang Mathias; Goldstein, IJ; Sandvig, Kirsten & Krengel, Ute (2011). MOA : structure-driven discovery of the proteolytic activity of a cytotoxic lectin. Show summary

  The Hemolytic Uremic Syndrome (HUS) is a disease characterized by hemolytic anemia, low platelet count and renal impairment. Based on the causative agent HUS can be classified as Shiga toxin-associated HUS (Stx-HUS) or non-Shiga toxin associated HUS (non-Stx-HUS), the former accounting for 70% of HUS cases in Europe and the North America. The therapy for HUS is still merely supportive, and there is currently no viable animal model (besides baboons) for a more in-depth systemic study of the disease. The Marasmius oreades agglutinin (MOA) is a two-domains Galα3Gal specific lectin, a sugar binding protein of non-immune origin, extracted from the fruiting body of the Marasmius oreades mushrooms. Other than showing the rare ability to specifically agglutinate erythrocytes of the blood group B, MOA parenterally administered to mice triggers a systemic effect which closely resembles the symptoms of Stx-HUS in humans. The recently determined x-ray crystallographic structure of MOA in complex with calcium and the blood group B branched trisaccharide (PDB id 2IHO) confirm the existence of a ricin B chain-like sugar binding domain and shows a C-terminal alpha/beta folded domain. A search for structural homologues on the DALI database using the coordinates of the C-terminal domain suggests a possible enzymatic function for the non-sugar binding domain, thus providing a further link to the Shiga toxin induced HUS. The investigation of the enzymatic activity of MOA has confirmed the structure-based functional hypothesis and it has shown that the protein behaves as a Ca2+-dependent cysteine protease. An initial characterization of the enzymatic activity has been performed, showing how the processing of the substrate is affected by the concentration of Ca2+, the presence of a reducing agent and other factors. At the same time, the cytotoxic activity of MOA on different cell types has been evaluated, showing the NIH3T3 cell line as the most sensitive among the tested targets; the incubation with MOA leads to cell detachment, preceded by a decrease in the level of protein and DNA synthesis.

• Cordara, Gabriele; Grahn, Elin; Jacobsen, Wolfgang Mathias; Goldstein, IJ; Sandvig, Kirsten & Krengel, Ute (2011). Marasmius oreades agglutinin (MOA) is a cytotoxic lectin with proteolytic activity. Show summary

  The Marasmius oreades mushroom lectin (MOA) is known since the 1950s for its blood group type B binding specificity. The three-dimensional structure of the lectin, recently determined by X-ray crystallography elucidated the details of its carbohydrate binding characteristics, and in particular how this lectin discriminates between blood group A and B structures. MOA’s C-terminal domain adopts an alpha/beta fold. This domain primarily serves as the dimerization interface for MOA protomers, although its structural similarity to hydrolytic enzymes suggests that it may exhibit additional functions. Here, we show that MOA indeed has a previously unknown proteolytic activity linked to its C-terminal domain, involving Cys215 as the catalytically active residue and a strict dependence on the calcium ion fulfilling a fundamental structural role.

• Cordara, Gabriele; Grahn, Elin; Jacobsen, Wolfgang Mathias; Goldstein, IJ; Sandvig, Kirsten & Krengel, Ute (2011). Marasmius oreades agglutinin (MOA): A lectin with a proteolytic domain.
• Cordara, Gabriele; Grahn, Elin; Jacobsen, Wolfgang Mathias; Goldstein, Irwin; Sandvig, Kirsten & Krengel, Ute (2011). MOA : structure-driven discovery of the proteolytic activity of a cytotoxic lectin. Show summary

  Lectins, sugar binding proteins of non-immune origin, are one of the many weapons used by plants and fungi to defend themselves against potential predators and parasites. This role is often fulfilled by the presence of a domain with an additional function besides the sugar binding domain. The Marasmius oreades agglutinin (MOA) is a Gal-α3Gal specific lectin extracted from the fruiting body of the Marasmius oreades mushroom. Other than showing the rare ability to specifically agglutinate erythrocytes of the blood group B (containing the recognized disaccharide on the non-reducing end of the B glycotope), parenterally administered MOA triggers a systemic effect in mice which closely resembles the symptoms of the shiga toxin-induced hemolytic uremic syndrome (Stx-HUS) in humans. The structure of MOA in complex with the branched blood group B trisaccharide and calcium, recently solved by X-ray crystallography, elucidated the fine details of the sugar binding specificity of the N-terminal ricin B chain-like domain and showed the existence of an alpha/beta hydrolase fold C-terminal domain involved in dimerization A search for structural homologues, using the coordinates of the C-terminal domain as the input for the DALI database, provided a significant number of top-ranking hits belonging to the family of the papain-like cysteine peptidates (clan CA). A notable feature is the conservation in MOA of two key residues of the catalytic triad (Cys215 and His257) while the third residue is substituted by an amino acid with similar properties (Glu274 in place of Asp). Starting from the structure-based functional hypothesis of the presence of a hydrolytic activity associated to the C-terminal domain, MOA was probed with a model substrate and found to be a calcium-dependent cysteine peptidase, with Cys215 acting as the catalytic residue.

• Cordara, Gabriele (2010). MOA - s sugar binding protein - From structure to hypotheses on function.
• Cordara, Gabriele; Grahn, Elin; Goldstein, IJ & Krengel, Ute (2010). MOA, a sugar binding protein - From structure to hypotheses on function.
• Cordara, Gabriele; Grahn, Elin; Jacobsen, Wolfgang Mathias; Goldstein, IJ; Sandvig, Kirsten & Krengel, Ute (2010). MOA – A cytotoxic lectin from a mushroom could provide an animal model for HUS/TPP. Show summary

  The Hemolytic Uremic Syndrome (HUS) is a disease characterized by hemolytic anemia, low platelet count and renal impairment. Based on the causative agent HUS can be classified as Shiga toxin-associated HUS (Stx-HUS) or non-Shiga toxin associated HUS (non-Stx-HUS), the former accounting for 70% of HUS cases in Europe and the North America. The therapy for HUS is still merely supportive, and there is currently no viable animal model (aside baboons) for a more in-depth systemic study of the disease. The Marasmius Oreades Agglutinin (MOA) is a two-domains Gal-alpha1,3Gal specific lectin, a sugar binding protein of non-immune origin, extracted from the fruiting body of the Marasmius oreades mushrooms. Other than showing the rare ability to specifically agglutinate erythrocytes of the blood group B, parenterally administered MOA triggers a systemic effect in mice which closely resembles the symptoms of Stx-HUS in humans. The recently determined x-ray crystallographic structure of MOA in complex with calcium and the blood group B branched trisaccharide suggests a possible enzymatic function for the non-sugar binding domain, thus providing a further link to the Shiga toxin induced HUS. The aim of this project is to investigate the nature of MOA’s enzymatic function along with structurally relevant determinant involved in the enzymatic activity and to determine the relationship between such activity and the cytotoxic effects.

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