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, 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

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    Abstract

    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.

    OriginalsprogEngelsk
    TidsskriftThe Biochemical journal
    Vol/bind465
    Udgave nummer2
    Sider (fra-til)259-270
    Antal sider12
    ISSN0264-6021
    DOI
    StatusUdgivet - 15. jan. 2015

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