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Ambidextrous binding of cell and membrane bilayers by soluble matrix metalloproteinase-12

Author

Listed:
  • Rama K. Koppisetti

    (University of Missouri)

  • Yan G. Fulcher

    (University of Missouri)

  • Alexander Jurkevich

    (Molecular Cytology Core, 120 Bond Life Sciences Center, University of Missouri)

  • Stephen H. Prior

    (University of Missouri)

  • Jia Xu

    (University of Missouri)

  • Marc Lenoir

    (College of Medical and Dental Sciences, School of Cancer Sciences, University of Birmingham, Edgbaston)

  • Michael Overduin

    (College of Medical and Dental Sciences, School of Cancer Sciences, University of Birmingham, Edgbaston)

  • Steven R. Van Doren

    (University of Missouri)

Abstract

Matrix metalloproteinases (MMPs) regulate tissue remodelling, inflammation and disease progression. Some soluble MMPs are inexplicably active near cell surfaces. Here we demonstrate the binding of MMP-12 directly to bilayers and cellular membranes using paramagnetic NMR and fluorescence. Opposing sides of the catalytic domain engage spin-labelled membrane mimics. Loops project from the β-sheet interface to contact the phospholipid bilayer with basic and hydrophobic residues. The distal membrane interface comprises loops on the other side of the catalytic cleft. Both interfaces mediate MMP-12 association with vesicles and cell membranes. MMP-12 binds plasma membranes and is internalized to hydrophobic perinuclear features, the nuclear membrane and inside the nucleus within minutes. While binding of TIMP-2 to MMP-12 hinders membrane interactions beside the active site, TIMP-2-inhibited MMP-12 binds vesicles and cells, suggesting compensatory rotation of its membrane approaches. MMP-12 association with diverse cell membranes may target its activities to modulate innate immune responses and inflammation.

Suggested Citation

  • Rama K. Koppisetti & Yan G. Fulcher & Alexander Jurkevich & Stephen H. Prior & Jia Xu & Marc Lenoir & Michael Overduin & Steven R. Van Doren, 2014. "Ambidextrous binding of cell and membrane bilayers by soluble matrix metalloproteinase-12," Nature Communications, Nature, vol. 5(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6552
    DOI: 10.1038/ncomms6552
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