%0 Journal Article %T New insights into the substrate specificity of macrophage elastase MMP-12 %+ Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR) %+ Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA) %+ Universidade de São Paulo = University of São Paulo (USP) %A Lamort, Anne-Sophie %A Gravier, Rodolphe %A Laffitte, Anni %A Juliano, Luiz %A Zani, Marie-Louise %A Moreau, Thierry %Z Conseil Régional Centre-Val de Loire Programme Investissement d'Avenir Grant Agreement Labex Mab'Improve ANR-10-LABX-53 %< avec comité de lecture %@ 1431-6730 %J Biological Chemistry %I De Gruyter %V 397 %N 5 %P 469-484 %8 2016-05 %D 2016 %R 10.1515/hsz-2015-0254 %M 26760307 %K enzyme specificity %K macrophage elastase %K MMP-12 %K peptide-protein docking %K substrate recognition %K obstructive pulmonary-disease %K human alpha-1-proteinase inhibitor %K integral membrane-proteins %K matrix metalloproteinase-12 %K alveolar macrophages %K expression %K emphysema %K peptide %K copd %K mice %Z Life Sciences [q-bio]/Biochemistry, Molecular BiologyJournal articles %X 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 ProX-X down arrow 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. %G English %2 https://u-bourgogne.hal.science/hal-01398704/document %2 https://u-bourgogne.hal.science/hal-01398704/file/2016_lamort_biol.chem_1.pdf %L hal-01398704 %U https://u-bourgogne.hal.science/hal-01398704 %~ INSERM %~ UNIV-BOURGOGNE %~ UNIV-TOURS %~ CNRS %~ INRA %~ AGREENIUM %~ INRAE %~ ANR %~ CEPR %~ TEST3-HALCNRS