New insights into the substrate specificity of macrophage elastase MMP-12

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dc.citation.issue5
dc.citation.volume397
dc.contributor.authorLamort, Anne-Sophie
dc.contributor.authorGravier, Rodolphe
dc.contributor.authorLaffitte, Anni
dc.contributor.authorJuliano, Luiz [UNIFESP]
dc.contributor.authorZani, Marie-Louise
dc.contributor.authorMoreau, Thierry
dc.coverageBerlin
dc.date.accessioned2020-07-22T13:23:00Z
dc.date.available2020-07-22T13:23:00Z
dc.date.issued2016
dc.description.abstractMacrophage 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.en
dc.description.affiliationAtlanbio, ZI de Brais 1 Rue Graham Bell, F-44600 St Nazaire, France
dc.description.affiliationUniv Bourgogne, INRA UMR1324, CNRS UMR6265, Ctr Sci Gout & Alimentat, F-21000 Dijon, France
dc.description.affiliationUniv Tours, Fac Med, CEPR UMR INSERM U1100, Equipe Mecanismes Proteolyt Inflammat 2, 10 Bd Tonnelle, F-37032 Tours, France
dc.description.affiliationUniv Sao Paulo, Escola Paulista Med, BR-04044020 Sao Paulo, Brazil
dc.description.affiliationUnifespUniv Sao Paulo, Escola Paulista Med, BR-04044020 Sao Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipConseil Regional Centre-Val de Loire
dc.description.sponsorshipprogramme Investissement d'Avenir Grant Agreement Labex Mab'Improve
dc.description.sponsorshipIDLabex Mab'Improve: ANR-10-LABX-53
dc.format.extent469-484
dc.identifierhttp://dx.doi.org/10.1515/hsz-2015-0254
dc.identifier.citationBiological Chemistry. Berlin, v. 397, n. 5, p. 469-484, 2016.
dc.identifier.doi10.1515/hsz-2015-0254
dc.identifier.issn1431-6730
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/55983
dc.identifier.wosWOS:000374975300007
dc.language.isoeng
dc.publisherWalter De Gruyter Gmbh
dc.relation.ispartofBiological Chemistry
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.subjectenzyme specificityen
dc.subjectmacrophage elastaseen
dc.subjectMMP-12en
dc.subjectpeptide-protein dockingen
dc.subjectsubstrate recognitionen
dc.titleNew insights into the substrate specificity of macrophage elastase MMP-12en
dc.typeinfo:eu-repo/semantics/article
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