Katrine Ter-Borch Gram Schjoldager

Katrine Ter-Borch Gram Schjoldager

Lektor - forfremmelsesprogrammet

Primære forskningsområder

The main goal of our research is to discover and dissect molecular protein functions that impact human physiology and common diseases and dispositions. My group focuses on post translational modifications and in particular protein glycosylation, merging protein biology, glycoscience, and biomedicine within classical cell biology. We use state-of-the-art gene engineering technologies, mass spectrometry and biophysical analysis in combination with animal and cell models to explore specific functional and structural impact of protein glycosylation as well as disease-causing driver functions of the enzymes controlling protein glycosylation. The three major research themes in my lab can be found under "Current project areas".

Aktuel forskning

1: Biological Functions of Glycans - Glycosylation serves to tune and diversify functions of proteins Schjoldager et al., 2020. Several illustrative examples with clear impact on disease, document the importance of different types of glycosylation in regulating protein functions, however, we are still at a stage of infancy in recognizing and appreciating the role of glycosylation in common diseases. My group has lead the mapping of the mammalian O- glycoproteome in tissues and biofluids and discovered O-glycans on important classes of proteins with functional roles Bennett et al., 2012; Schjoldager et al., 2010, 2012, 2015; Steentoft et al., 2013; Goth et al., 2015, 2017, 2018; King et al., 2018; Khetarpal et al., 2016; Hansen et al., 2017; Wang et al., 2018, Tian et al., 2019; Hansen et al., 2019; Madsen et al. 2020).  At the specific glycosites, glycostructures (core-structures and capping) can determine the ultimate outcome and regulatory potential of glycosylation and there is abundant evidence that the structure of glycans on proteins regulates diverse protein interactions and biological functions. In this line, through genetic engineering in cell lines, we can produce glycoproteins with specific glycosylation sites and defined glycan structures for biophysical and biochemical analysis as well as application in biological models. In this project line we are following the role of specific glycoproteins to discover other fundamental functions of O-glycosylation.

 

2: Protein-protein interactions in the context of complex carbohydrates – This project line aims to analyse and characterise the molecular mechanisms underlying glycoprotein functions. Protein-protein interactions represent a fundamental aspect of cell biology and great efforts are devoted to exploring and defining the protein interactome. Common for most current analytic strategies is that these ignore prevalent PTMs like glycosylation that affect protein biophysical properties and structure and serve essential roles in fine-tuning protein functions (Schjoldager et al., 2020). We have spearheaded the mapping of the mammalian glycoproteome in tissues and biofluids and discovered that O-glycosylation is a major PTM found on important classes of proteins both soluble and embedded in the plasma membrane and glycocalyx (Goth et al., 2018; Hansen et al., 2017; Khetarpal et al., 2016; King et al., 2017; Madsen et al., 2020). Protein glycosylation is well-documented to be important for the single cell and the complex organism and when glycosylation goes awry, disease develops as described above. Depending on how affected the glycosylation apparatus is, subtle phenotypes as exemplified by familial hyperphosphatemia calcinosis with loss of GALNT3 may develop, but when protein glycosylation is more broadly impaired severe diseases develop, most with clear metabolic and neurological involvement, and total loss of protein glycosylation is incompatible with life. Progress in discerning aetiology and approaching molecular mechanisms involving glycoproteins in neuronal development and metabolic signalling has been halted by technical limitations in studying protein glycosylation. In this project line we are exploring O-glycosylation sites in neuronal and neuroendocrine cells and tissues as a discovery platform fornovel protein functions, protein-protein interactions, and rational design of protein therapeutics for a range of common diseases.

 

3: Regulation of protein O-glycosylation and genetic deficiencies- Mutations leading to structural defects in glycosyltransferase genes and severe multisystemic diseases as described above are extremely rare (Hansen et al., 2014; Zilmer et al., 2020). In contrast, genome-wide association studies (GWAS) quite frequently find that single nucleotide polymorphisms (SNPs) in glycosyltransferase genes, and in particular GALNT genes, associate with complex traits or common diseases/conditions like kidney disease (GALNT11), osteoporosis (GALNT3), dyslipidemia (GALNT2) and body mass index (GALNT10) (Joshi et al., 2018). To validate these candidate genes the task is to identify specific roles of individual GALNTs to uncover disease-causing mechanisms and explore diagnostic and therapeutic options. This task may be guided by phenotypic characteristics associated with complete deficiencies of GALNT genes in animal models and rare patients, as well as from GWAS phenotypic traits. We are using such guidance and provided the first molecular dissections of highly specific functions of GALNTs that cause human diseases (Khetarpal et al., 2016; Wang et al., 2018, Tian et al., 2019, Zilmer et al., 2020) supporting the hypothesis that dysregulation of GALNTs underlie a range of common complex diseases through improper fine-tuning of protein functions. To explore this concept further, we are developing glycoengineered cell and animal models that will provide us with much needed basic insight into how glycosyltransferases are regulated at the transcript and enzyme activity level and accordingly expand the workspace for discovery and design of selective inhibitors of individual GALNT enzymes needed for in vivo studies.

 

Undervisnings- og vejledningsområder

Pre-graduate teaching in Cell Biology and post-graduate teaching in Glycobiology at the Faculty of Health Sciences.

Supervisor/Co-supervisor - PhD-students: Asli Bahar Topaktas (present), Kasper Budolph Pedersen (present), Lasse Holst Hansen (past), John Birger Hintze (past), Yun Kong (past), Christoffer Goth (past), Sarah King-Smith (past), master students (Thomas Daugbjerg Madsen (past), Catharina Steentoft (past) and Lasse Holst Hansen (past), 1 bachelor student (Thomas Daugbjerg Madsen (past)), 1 Erasmus-student (Nathalie Petronella De Wagenaar (past))

Udvalgte publikationer

  1. Udgivet

    Cellular cross talk in the small intestinal mucosa: postnatal lymphocytic immigration elicits a specific epithelial transcriptional response

    Schjoldager, Katrine Ter-Borch Gram, Maltesen, H. R., Balmer, S., Lund, L. R., Claesson, Mogens Helweg, Sjöström, H., Troelsen, J. T. & Olsen, Jørgen, 2008, I: American Journal of Physiology: Gastrointestinal and Liver Physiology. 294, 6, s. G1335-43

    Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

  2. Udgivet

    Rescue of Drosophila Melanogaster l(2)35Aa lethality is only mediated by polypeptide GalNAc-transferase pgant35A, but not by the evolutionary conserved human ortholog GalNAc-transferase-T11

    Bennett, Eric Paul, Chen, Y., Schwientek, T., Mandel, Ulla, Schjoldager, Katrine Ter-Borch Gram, Cohen, S. M. & Clausen, Henrik, 2010, I: Glycoconjugate Journal. 27, 4, s. 435-44 9 s.

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  3. Udgivet

    Characterization of an immunodominant cancer-specific O-glycopeptide epitope in murine podoplanin (OTS8)

    Steentoft, C., Schjoldager, Katrine Ter-Borch Gram, Cló, E., Mandel, Ulla, Levery, S. B., Pedersen, J. W., Jensen, Knud Jørgen, Blixt, O. & Clausen, Henrik, 2010, I: Glycoconjugate Journal. 27, 6, s. 571-82 11 s.

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  4. Udgivet

    O-Glycosylation Modulates Proprotein Convertase Activation of Angiopoietin-like Protein 3: POSSIBLE ROLE OF POLYPEPTIDE GalNAc-TRANSFERASE-2 IN REGULATION OF CONCENTRATIONS OF PLASMA LIPIDS

    Schjoldager, Katrine Ter-Borch Gram, Vester-Christensen, M. B., Bennett, Eric Paul, Levery, S. B., Schwientek, T., Yin, W., Blixt, O. & Clausen, Henrik, 2010, I: Journal of Biological Chemistry. 285, 47, s. 36293-303 10 s.

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  5. Udgivet

    Lectin Domains of Polypeptide GalNAc Transferases Exhibit Glycopeptide Binding Specificity

    Pedersen, J. W., Bennett, Eric Paul, Schjoldager, Katrine Ter-Borch Gram, Meldal, Morten Peter, Holmér, A. P., Blixt, O., Cló, E., Levery, S. B., Clausen, Henrik & Wandall, Hans H., 16 sep. 2011, I: The Journal of Biological Chemistry. 286, 37, s. 32684-96 13 s.

    Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

  6. Udgivet

    A systematic study of site-specific GalNAc-type O-glycosylation modulating proprotein convertase processing

    Schjoldager, Katrine Ter-Borch Gram, Vester-Christensen, M. B., Goth, C. K., Petersen, T. N., Brunak, Søren, Bennett, Eric Paul, Levery, S. B. & Clausen, Henrik, 18 nov. 2011, I: Journal of Biological Chemistry. 286, 46, s. 40122-32 11 s.

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  7. Udgivet

    Mining the O-glycoproteome using zinc-finger nuclease-glycoengineered SimpleCell lines

    Steentoft, C., Vakhrushev, Sergey, Vester-Christensen, M. B., Schjoldager, Katrine Ter-Borch Gram, Kong, Y., Bennett, Eric Paul, Mandel, Ulla, Wandall, Hans H., Levery, S. B. & Clausen, Henrik, okt. 2011, I: Nature Methods. 8, 11, s. 977-82 6 s.

    Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

  8. Udgivet
  9. Udgivet

    Probing isoform-specific functions of polypeptide GalNAc-transferases using zinc finger nuclease glycoengineered SimpleCells

    Schjoldager, Katrine Ter-Borch Gram, Vakhrushev, Sergey, Kong, Y., Steentoft, C., Nudelman, A. S., Pedersen, N. B., Wandall, Hans H., Mandel, Ulla, Bennett, Eric Paul, Levery, S. B. & Clausen, Henrik, jun. 2012, I: Proceedings of the National Academy of Sciences USA (PNAS). 109, 25, s. 9893-8 6 s.

    Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

  10. Udgivet

    Site-specific protein O-glycosylation modulates proprotein processing - Deciphering specific functions of the large polypeptide GalNAc-transferase gene family

    Schjoldager, Katrine Ter-Borch Gram & Clausen, Henrik, sep. 2012, I: BBA General Subjects. 1820, 12, s. 2079-94 16 s.

    Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

  11. Udgivet

    Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology

    Steentoft, C., Vakhrushev, Sergey, Joshi, Hiren Jitendra, Kong, Y., Vester-Christensen, M. B., Schjoldager, Katrine Ter-Borch Gram, Lavrsen, K., Dabelsteen, Sally, Pedersen, N. B., da Silva, L. P. M., Gupta, R., Bennett, Eric Paul, Mandel, Ulla, Brunak, Søren, Wandall, Hans H., Levery, S. B. & Clausen, Henrik, 15 maj 2013, I: E M B O Journal. 32, 10, s. 1478-1488 11 s.

    Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

ID: 920646