Vandooren, Jennifer2; Born, Benjamin2; Solomonov, Inna2; Zajac, Ewa2; Saldova, Radka2; Senske, Michael2; Ugarte-Berzal, Estefanía2; Martens, Erik2; Van den Steen, Philippe E2; Van Damme, Jo2; Garcia-Pardo, Angeles2; Froeyen, Matheus2; Deryugina, Elena I2; Quigley, James P2; Moestrup, Søren K3; Rudd, Pauline M2; Sagi, Irit2; Opdenakker, Ghislain2
1 Department of Biomedicine - Forskning og uddannelse, Vest, Department of Biomedicine, Health, Aarhus University2 unknown3 Department of Biomedicine - Forskning og uddannelse, Vest, Department of Biomedicine, Health, Aarhus University
Gelatinase B/matrix metalloproteinase-9 (MMP-9) (EC 184.108.40.206) 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.
Biochemical Journal, 2015, Vol 465, Issue 2, p. 259-70