Plasmin releases the anti-tumor peptide from the NC1 domain of collagen XIX
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Jean-Baptiste Oudart1,3, Sylvie Brassart-Pasco1, Alexia Vautrin1, Christèle Sellier1, Carine Machado2, Aurelie Dupont-Deshorgue1, Bertrand Brassart1, Stéphanie Baud1,4, Manuel Dauchez1,4, Jean-Claude Monboisse1,3, Dominique Harakat2, François-Xavier Maquart1,3, Laurent Ramont1,3
1Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France
2Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR N°7312, Faculté de Pharmacie, Reims, France
3CHU de Reims, Laboratoire Central de Biochimie, Reims, France
4Plateau de Modélisation Moléculaire Multi-échelle, UFR Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, Reims, France
Laurent Ramont, e-mail: [email protected]
Keywords: Collagen XIX, NC1 domain, Plasmin, Proteolysis, Tumor invasion, type I β-turn
Received: October 16, 2014 Accepted: December 05, 2014 Published: February 13, 2015
During tumor invasion, tumor cells degrade the extracellular matrix. Basement membrane degradation is responsible for the production of peptides with anti-tumor properties. Type XIX collagen is associated with basement membranes in vascular, neuronal, mesenchymal and epithelial tissues. Previously, we demonstrated that the non-collagenous NC1, C-terminal, domain of collagen XIX [NC1(XIX)] inhibits the migration capacities of tumor cells and exerts a strong inhibition of tumor growth. Here, we demonstrate that plasmin, one of the most important enzyme involved in tumor invasion, was able to release a fragment of NC1(XIX), which retained the anti-tumor activity. Molecular modeling studies showed that NC1(XIX) and the anti-tumor fragment released by plasmin (F4) adopted locally the same type I β-turn conformation. This suggests that the anti-tumor effect is conformation-dependent. This study demonstrates that collagen XIX is a novel proteolytic substrate for plasmin. Such release may constitute a defense of the organism against tumor invasion.
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