Sulfated glycosaminoglycans inhibit transglutaminase 2 by stabilizing its closed conformation

Transglutaminases (TGs) catalyze the covalent crosslinking of proteins via isopeptide bonds. The most prominent isoform, TG2, is associated with physiological processes such as extracellular matrix (ECM) stabilization and plays a crucial role in the pathogenesis of e.g. fibrotic diseases, cancer and...

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Published in:Scientific reports 2022-08, Vol.12 (1), p.13326-13326, Article 13326
Main Authors: Müller, Claudia Damaris, Ruiz-Gómez, Gloria, Cazzonelli, Sophie, Möller, Stephanie, Wodtke, Robert, Löser, Reik, Freyse, Joanna, Dürig, Jan-Niklas, Rademann, Jörg, Hempel, Ute, Pisabarro, M. Teresa, Vogel, Sarah
Format: Article
Language:English
Subjects:
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Binding sites
Cancer
Celiac disease
Cell adhesion & migration
Chemical bonds
Chondroitin sulfate
Conformation
Enzymes
Extracellular matrix
Glycosaminoglycans
Heparan sulfate
Heparin
Humanities and Social Sciences
Hyaluronic acid
Molecular modelling
multidisciplinary
Peptides
Physiology
Proteins
Science
Science (multidisciplinary)
Sulfates
Transglutaminase 2
Wound healing
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Summary:Transglutaminases (TGs) catalyze the covalent crosslinking of proteins via isopeptide bonds. The most prominent isoform, TG2, is associated with physiological processes such as extracellular matrix (ECM) stabilization and plays a crucial role in the pathogenesis of e.g. fibrotic diseases, cancer and celiac disease. Therefore, TG2 represents a pharmacological target of increasing relevance. The glycosaminoglycans (GAG) heparin (HE) and heparan sulfate (HS) constitute high-affinity interaction partners of TG2 in the ECM. Chemically modified GAG are promising molecules for pharmacological applications as their composition and chemical functionalization may be used to tackle the function of ECM molecular systems, which has been recently described for hyaluronan (HA) and chondroitin sulfate (CS). Herein, we investigate the recognition of GAG derivatives by TG2 using an enzyme-crosslinking activity assay in combination with in silico molecular modeling and docking techniques. The study reveals that GAG represent potent inhibitors of TG2 crosslinking activity and offers atom-detailed mechanistic insights.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-17113-2