Differential Processing of α- and β-Defensin Precursors by Matrix Metalloproteinase-7 (MMP-7)
| Autor: | Carole L. Wilson, Amy P. Schmidt, Nicola Ferri, Emma Pirilä, William C. Parks, Erika V. Valore, Tomas Ganz, Timo Sorsa |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
alpha-Defensins
beta-Defensins Peptide Biology Matrix metalloproteinase Cleavage (embryo) Biochemistry Catalysis Cell Line Mice 03 medical and health sciences 0302 clinical medicine Animals Humans Moiety Post-translational regulation Protein Precursors Molecular Biology Defensin 030304 developmental biology chemistry.chemical_classification 0303 health sciences Enzyme Catalysis and Regulation integumentary system fungi Cell Biology respiratory system Protein Structure Tertiary Amino acid Enzyme chemistry Matrix Metalloproteinase 7 030220 oncology & carcinogenesis |
| Zdroj: | Journal of Biological Chemistry. 284:8301-8311 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m809744200 |
| Popis: | Proteolytic processing of defensins is a critical mode of posttranslational regulation of peptide activity. Because mouse alpha-defensin precursors are cleaved and activated by matrix metalloproteinase-7 (MMP-7), we determined if additional defensin molecules, namely human neutrophil defensin pro-HNP-1 and beta-defensins, are targets for MMP-7. We found that MMP-7 cleaves within the pro-domain of the HNP-1 precursor, a reaction that does not generate the mature peptide but produces a 59-amino acid intermediate. This intermediate, which retains the carboxyl-terminal end of the pro-domain, had antimicrobial activity, indicating that the residues important for masking defensin activity reside in the amino terminus of this domain. Mature HNP-1 was resistant to processing by MMP-7 unless the peptide was reduced and alkylated, demonstrating that only the pro-domain of alpha-defensins is normally accessible for cleavage by this enzyme. From the 47-residue HBD-1 precursor, MMP-7 catalyzed removal of 6 amino acids from the amino terminus. Neither a 39-residue intermediate form of HBD-1 nor the mature 36-residue form of HBD-1 was cleaved by MMP-7. In addition, both pro-HBD-2, with its shorter amino-terminal extension, and pro-HBD-3 were resistant to MMP-7. However, human and mouse beta-defensin precursors that lack disulfide bonding contain a cryptic MMP-7-sensitive site within the mature peptide moiety. These findings support and extend accumulating evidence that the native three-dimensional structure of both alpha- and beta-defensins protects the mature peptides against proteolytic processing by MMP-7. We also conclude that sites for MMP-7 cleavage are more common at the amino termini of alpha-defensin rather than beta-defensin precursors, and that catalysis at these sites in alpha-defensin pro-domains results in acquisition of defensin activity. |
| Databáze: | OpenAIRE |
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