Plasmin releases the anti-tumor peptide from the NC1 domain of collagen XIX

Abstract

// Jean-Baptiste Oudart 1, 3 , Sylvie Brassart-Pasco 1 , Alexia Vautrin 1 , Christèle Sellier 1 , Carine Machado 2 , Aurelie Dupont-Deshorgue 1 , Bertrand Brassart 1 , Stéphanie Baud 1, 4 , Manuel Dauchez 1, 4 , Jean-Claude Monboisse 1, 3 , Dominique Harakat 2 , François-Xavier Maquart 1, 3 , Laurent Ramont 1, 3 1 Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France 2 Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR N°7312, Faculté de Pharmacie, Reims, France 3 CHU de Reims, Laboratoire Central de Biochimie, Reims, France 4 Plateau de Modélisation Moléculaire Multi-échelle, UFR Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, Reims, France Correspondence to: Laurent Ramont, e-mail: lramont@chu-reims.fr 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 ABSTRACT 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.