Plasmin releases the anti-tumor peptide from the NC1 domain of collagen XIX
Jean-Baptiste Oudart1,2, Sylvie Brassart-Pasco1, Alexia Vautrin1
1Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France.
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.
Insights
Collagen XIX releases an anti-tumor fragment via plasmin, inhibiting tumor cell migration and growth. This suggests a natural defense mechanism against cancer invasion.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Tumor cells degrade the extracellular matrix during invasion.
- Basement membrane degradation yields peptides with anti-tumor properties.
- Type XIX collagen (COL19) is a basement membrane component.
Purpose of the Study:
- To investigate the interaction between plasmin and collagen XIX.
- To characterize the anti-tumor activity of collagen XIX fragments.
- To explore the structural basis of collagen XIX's anti-tumor effects.
Main Methods:
- Plasmin digestion of collagen XIX.
- Analysis of released fragments for anti-tumor activity.
- Molecular modeling of collagen XIX domains and fragments.
Main Results:
- Plasmin releases a fragment (F4) from collagen XIX's NC1(XIX) domain.
- The released fragment F4 retains anti-tumor activity, inhibiting tumor cell migration and growth.
- Molecular modeling revealed a conserved β-turn conformation in NC1(XIX) and F4, suggesting conformation-dependent activity.
Conclusions:
- Collagen XIX is a novel substrate for plasmin.
- Plasmin-mediated release of collagen XIX fragments represents a potential endogenous anti-tumor defense mechanism.
- The anti-tumor activity of collagen XIX is conformation-dependent.
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