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New insights into the substrate specificity of macrophage elastase MMP-12
- Source :
- Biological Chemistry, Biological Chemistry, De Gruyter, 2016, 397 (5), ⟨10.1515/hsz-2015-0254⟩, Biological Chemistry 5 (397), 469-484. (2016), Biological Chemistry, De Gruyter, 2016, 397 (5), 〈10.1515/hsz-2015-0254〉, Biological Chemistry, 2016, 397 (5), pp.469-484. ⟨10.1515/hsz-2015-0254⟩, Biological Chemistry, De Gruyter, 2016, 397 (5), pp.469-484. ⟨10.1515/hsz-2015-0254⟩
- Publication Year :
- 2016
- Publisher :
- Walter de Gruyter GmbH, 2016.
-
Abstract
- Macrophage elastase, or MMP-12, is mainly produced by alveolar macrophages and is believed to play a major role in the development of chronic obstructive pulmonary disease (COPD). The catalytic domain of MMP-12 is unique among MMPs in that it is very highly active on numerous substrates including elastin. However, measuring MMP-12 activity in biological fluids has been hampered by the lack of highly selective substrates. We therefore synthesized four series of fluorogenic peptide substrates based on the sequences of MMP-12 cleavage sites in its known substrates. Human MMP-12 efficiently cleaved peptide substrates containing a Pro at P3 in the sequence Pro-X-X↓Leu but lacked selectivity towards these substrates compared to other MMPs, including MMP-2, MMP-7, MMP-9 and MMP-13. On the contrary, the substrate Abz-RNALAVERTAS-EDDnp derived from the CXCR5 chemokine was the most selective substrate for MMP-12 ever reported. All substrates were cleaved more efficiently by full-length MMP-12 than by its catalytic domain alone, indicating that the C-terminal hemopexin domain influences substrate binding and/or catalysis. Docking experiments revealed unexpected interactions between the peptide substrate Abz-RNALAVERTAS-EDDn and MMP-12 residues. Most of our substrates were poorly cleaved by murine MMP-12 suggesting that human and murine MMP-12 have different substrate specificities despite their structural similarity.
- Subjects :
- 0301 basic medicine
Clinical Biochemistry
Organic chemistry
Peptide
Matrix metalloproteinase
Bioinformatics
Biochemistry
enzyme specificity
macrophage elastase
mmp-12
peptide-protein docking
substrate recognition
Substrate Specificity
Catalytic Domain
Integral membrane protein
chemistry.chemical_classification
biology
Biologie du développement
Hemopexin
Development Biology
peptide
integral membrane-proteins
Molecular Docking Simulation
emphysema
MMP-12
Oligopeptides
mice
Structural similarity
matrix metalloproteinase-12
Macrophage elastase
03 medical and health sciences
Species Specificity
Matrix Metalloproteinase 12
expression
[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Molecular Biology
Fluorescent Dyes
human alpha-1-proteinase inhibitor
copd
alveolar macrophages
Chimie organique
030104 developmental biology
chemistry
Docking (molecular)
Biocatalysis
biology.protein
obstructive pulmonary-disease
Elastin
Subjects
Details
- ISSN :
- 14374315 and 14316730
- Volume :
- 397
- Database :
- OpenAIRE
- Journal :
- Biological Chemistry
- Accession number :
- edsair.doi.dedup.....1009be1e41f7d2acfee9155d6beb28b1