β1,6-GlcNAc Linkage to the Core Glycan on TIMP-1 Affects Its Gelatinase Inhibitory Activities: Aberrantly Glycosylated TIMP-1-MMP2 Complex Modeling Shows Weaker Interaction Compared to Bi-antennary Glycosylated TIMP-1

Jin Kak Lee, Won Seok Han, Jun Seok Lee, Yong Sam Kim, Jeong Heon Ko, Jong Shin Yoo, Chang No Yoon

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes that can regulate the tumor microenvironment. Metalloproteinase-1 (TIMP-1) is a MMP inhibitor that plays a critical role in the invasion and migration of cancer cells. N-acetylglucosaminyltransferase-V (GnT-V) catalyzes the attachment of a β1,6-N-acetylglucosamine (GlcNAc) linkage to the core glycan, and TIMP-1 has identified target proteins for GnT-V. Recent research reveals that aberrantly glycosylated TIMP-1 showed a weaker inhibition on gelatinase, and that this aberrancy of glycosylation was closely related with cancer cell invasion and metastasis. However, the mechanism of action of glycan modification is not known at the molecular level. In this study, the bi-antennary and aberrant glycan structures were determined by mass spectrometry, and a model of the glycosylated TIMP-1-MMP2 complex was constructed to study the effects of glycosylation on the inhibitory activity of TIMP-1. Then this model was used to examine the effects of attaching a β1,6-GlcNAc linkage to the core glycan on the interaction of TIMP-1 with MMP2. The gelatinase inhibitory activity is decreased when additional a β1,6-GlcNAc moiety is linked to the core glycan on TIMP-1. The modeled structure of the glycosylated TIMP-1-MMP2 complex reveals how aberrant N-linked glycan hinders the interaction of these molecules.

Original languageEnglish
Pages (from-to)384-388
Number of pages5
JournalBulletin of the Korean Chemical Society
Volume38
Issue number3
DOIs
Publication statusPublished - 2017 Mar 1
Externally publishedYes

Keywords

  • Glycan interaction
  • Glycan structure
  • Metalloproteinase-1
  • β1,6-N-acetylglucosamine linkage

ASJC Scopus subject areas

  • Chemistry(all)

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