Søren Kragh Moestrup

Circular trimers of gelatinase B/matrix metalloproteinase-9 constitute a distinct population of functional enzyme molecules differentially regulated by tissue inhibitor of metalloproteinases-1

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Jennifer Vandooren, Unknown
  • Benjamin Born, Unknown
  • Inna Solomonov, Unknown
  • Ewa Zajac
  • ,
  • Radka Saldova, Unknown
  • Michael Senske, Unknown
  • Estefanía Ugarte-Berzal, Unknown
  • Erik Martens, Unknown
  • Philippe E Van den Steen
  • ,
  • Jo Van Damme, Unknown
  • Angeles Garcia-Pardo, Unknown
  • Matheus Froeyen, Unknown
  • Elena I Deryugina
  • ,
  • James P Quigley
  • ,
  • Søren K Moestrup
  • Pauline M Rudd
  • ,
  • Irit Sagi, Unknown
  • Ghislain Opdenakker

Gelatinase B/matrix metalloproteinase-9 (MMP-9) (EC 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.

Original languageEnglish
JournalBiochemical Journal
Pages (from-to)259-70
Number of pages12
Publication statusPublished - 15 Jan 2015

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