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Nat Commun. 2017 Nov 14;8(1):1483. doi: 10.1038/s41467-017-01525-0.

Network inference from glycoproteomics data reveals new reactions in the IgG glycosylation pathway.

Author information

1
Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany.
2
Genos Glycoscience Research Laboratory, 10000, Zagreb, Croatia.
3
Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000, Zagreb, Croatia.
4
Institute of Epidemiology 2, Research Unit Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany.
5
Institute of Epidemiology 2, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany.
6
Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014, Oulu, Finland.
7
Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA.
8
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, EH8 9AG, Edinburgh, UK.
9
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU, Edinburgh, UK.
10
Faculty of Science, University of Split, 21000, Split, Croatia.
11
Intellomics Ltd., 10000, Zagreb, Croatia.
12
Leiden University Medical Center, 2333, ZA Leiden, The Netherlands.
13
University of Split School of Medicine, 21000, Split, Croatia.
14
Gen-info Ltd., 10000, Zagreb, Croatia.
15
German Center for Diabetes Research (DZD), 40225, Düsseldorf, Germany.
16
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany.
17
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians Universität, 81577, Munich, Germany.
18
Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany.
19
Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CG, Utrecht, The Netherlands.
20
Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997, Moscow, Russia.
21
Department of Mathematics, Technical University Munich, 85748, Garching bei München, Germany.
22
Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany. jan.krumsiek@helmholtz-muenchen.de.
23
German Center for Diabetes Research (DZD), 40225, Düsseldorf, Germany. jan.krumsiek@helmholtz-muenchen.de.

Abstract

Immunoglobulin G (IgG) is a major effector molecule of the human immune response, and aberrations in IgG glycosylation are linked to various diseases. However, the molecular mechanisms underlying protein glycosylation are still poorly understood. We present a data-driven approach to infer reactions in the IgG glycosylation pathway using large-scale mass-spectrometry measurements. Gaussian graphical models are used to construct association networks from four cohorts. We find that glycan pairs with high partial correlations represent enzymatic reactions in the known glycosylation pathway, and then predict new biochemical reactions using a rule-based approach. Validation is performed using data from a GWAS and results from three in vitro experiments. We show that one predicted reaction is enzymatically feasible and that one rejected reaction does not occur in vitro. Moreover, in contrast to previous knowledge, enzymes involved in our predictions colocalize in the Golgi of two cell lines, further confirming the in silico predictions.

PMID:
29133956
PMCID:
PMC5684356
DOI:
10.1038/s41467-017-01525-0
[Indexed for MEDLINE]
Free PMC Article

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