The presence of outer arm fucose residues on the N -glycans of tissue inhibitor of metalloproteinases-1 reduces its activity

Han Ie Kim, Radka Saldova, Jun Hyoung Park, Young Hun Lee, David J. Harvey, Mark R. Wormald, Kieran Wynne, Giuliano Elia, Hwa Jung Kim, Pauline M. Rudd, Seung Taek Lee

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Abstract

Tissue inhibitor of metalloproteinases-1 (TIMP-1) inhibits matrix metalloproteinases (MMPs) by binding at a 1:1 stoichiometry. Here we have shown the involvement of N-glycosylation in the MMP inhibitory ability of TIMP-1. TIMP-1, purified from HEK 293 cells overexpressing TIMP-1 (293 TIMP-1), showed less binding and inhibitory abilities to MMPs than TIMP-1 purified from fibroblasts or SF9 insect cells infected with TIMP-1 baculovirus. Following deglycosylation of TIMP-1, all forms of TIMP-1 showed similar levels of MMP binding and inhibition, suggesting that glycosylation is involved in the regulation of these TIMP-1 activities. Analysis of the N-glycan structures showed that SF9 TIMP-1 has the simplest N-glycan structures, followed by fibroblast TIMP-1 and 293 TIMP-1, in order of increasing complexity in their N-glycan structures. Further analyses showed that cleavage of outer arm fucose residues from the N-glycans of 293 TIMP-1 or knockdown of both FUT4 and FUT7 (which encode for fucosyltransferases that add outer arm fucose residues to N-glycans) enhanced the MMP-binding and catalytic abilities of 293 TIMP-1, bringing them up to the levels of the other TIMP-1. These results demonstrate that the ability of TIMP-1 to inhibit MMPs is at least in part regulated by outer arm fucosylation of its N-glycans.

Original languageEnglish
Pages (from-to)3547-3560
Number of pages14
JournalJournal of Proteome Research
Volume12
Issue number8
DOIs
Publication statusPublished - 2013 Aug 2

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Chemistry(all)

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    Kim, H. I., Saldova, R., Park, J. H., Lee, Y. H., Harvey, D. J., Wormald, M. R., Wynne, K., Elia, G., Kim, H. J., Rudd, P. M., & Lee, S. T. (2013). The presence of outer arm fucose residues on the N -glycans of tissue inhibitor of metalloproteinases-1 reduces its activity. Journal of Proteome Research, 12(8), 3547-3560. https://doi.org/10.1021/pr400276r