Gelatinase B/matrix metalloproteinase-9 (MMP-9) (EC 3.4.24.35) cleaves many substrates and is produced by most cell types as a zymogen, proMMP-9, in complex with the tissue inhibitor of metalloproteinases-1 (TIMP-1). Natural proMMP-9 occurs as monomers, homomultimers and heterocomplexes, but our knowledge about the overall structure of proMMP-9 monomers and multimers is limited. We investigated biochemical, biophysical and functional characteristics of zymogen and activated forms of MMP-9 monomers and multimers. In contrast with a conventional notion of a dimeric nature of MMP-9 homomultimers, we demonstrate that these are reduction-sensitive trimers. Based on the information from electrophoresis, AFM and TEM, we generated a 3D structure model of the proMMP-9 trimer. Remarkably, the proMMP-9 trimers possessed a 50-fold higher affinity for TIMP-1 than the monomers. In vivo, this finding was reflected in a higher extent of TIMP-1 inhibition of angiogenesis induced by trimers compared with monomers. Our results show that proMMP-9 trimers constitute a novel structural and functional entity that is differentially regulated by TIMP-1.
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Research Article|
January 06 2015
Circular trimers of gelatinase B/matrix metalloproteinase-9 constitute a distinct population of functional enzyme molecules differentially regulated by tissue inhibitor of metalloproteinases-1
Jennifer Vandooren;
Jennifer Vandooren
*Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, B-3000 Leuven, Belgium
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Benjamin Born;
Benjamin Born
†Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
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Inna Solomonov;
Inna Solomonov
†Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
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Ewa Zajac;
Ewa Zajac
‡Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, U.S.A.
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Radka Saldova;
Radka Saldova
§NIBRT GlycoScience Group, National Institute for Bioprocessing Research and Training, Fosters Avenue, Mount Merrion, Blackrock, Dublin 4, Ireland
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Michael Senske;
Michael Senske
†Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
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Estefanía Ugarte-Berzal;
Estefanía Ugarte-Berzal
║Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), 28040 Madrid, Spain
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Erik Martens;
Erik Martens
*Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, B-3000 Leuven, Belgium
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Philippe E. Van den Steen;
Philippe E. Van den Steen
*Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, B-3000 Leuven, Belgium
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Jo Van Damme;
Jo Van Damme
**Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, KU Leuven, B-3000 Leuven, Belgium
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Angeles Garcia-Pardo;
Angeles Garcia-Pardo
║Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), 28040 Madrid, Spain
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Matheus Froeyen;
Matheus Froeyen
††Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, University of Leuven, KU Leuven, B-3000 Leuven, Belgium
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Elena I. Deryugina;
Elena I. Deryugina
‡Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, U.S.A.
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James P. Quigley;
James P. Quigley
‡Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, U.S.A.
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Søren K. Moestrup;
Søren K. Moestrup
‡‡Department of Biomedicine, University of Aarhus, DK-8000 Aarhus C, Denmark
§§Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsløws Vej 21–25, DK-5000 Odense C, Denmark
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Pauline M. Rudd;
Pauline M. Rudd
§NIBRT GlycoScience Group, National Institute for Bioprocessing Research and Training, Fosters Avenue, Mount Merrion, Blackrock, Dublin 4, Ireland
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Irit Sagi;
Irit Sagi
†Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
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Ghislain Opdenakker
Ghislain Opdenakker
1
*Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, B-3000 Leuven, Belgium
1To whom correspondence should be addressed (email ghislain.opdenakker@rega.kuleuven.be).
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Publisher: Portland Press Ltd
Received:
March 31 2014
Revision Received:
October 21 2014
Accepted:
October 31 2014
Accepted Manuscript online:
October 31 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem J (2015) 465 (2): 259–270.
Article history
Received:
March 31 2014
Revision Received:
October 21 2014
Accepted:
October 31 2014
Accepted Manuscript online:
October 31 2014
Citation
Jennifer Vandooren, Benjamin Born, Inna Solomonov, Ewa Zajac, Radka Saldova, Michael Senske, Estefanía Ugarte-Berzal, Erik Martens, Philippe E. Van den Steen, Jo Van Damme, Angeles Garcia-Pardo, Matheus Froeyen, Elena I. Deryugina, James P. Quigley, Søren K. Moestrup, Pauline M. Rudd, Irit Sagi, Ghislain Opdenakker; Circular trimers of gelatinase B/matrix metalloproteinase-9 constitute a distinct population of functional enzyme molecules differentially regulated by tissue inhibitor of metalloproteinases-1. Biochem J 15 January 2015; 465 (2): 259–270. doi: https://doi.org/10.1042/BJ20140418
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