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

Nat Commun. 2014 Nov 21;5:5552. doi: 10.1038/ncomms6552.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Membrane / metabolism*
  • HeLa Cells
  • Heparan Sulfate Proteoglycans / metabolism
  • Humans
  • Lipid Bilayers / metabolism*
  • Macrophages / immunology
  • Matrix Metalloproteinase 12 / metabolism*
  • Mice
  • Models, Molecular
  • Multiprotein Complexes / metabolism
  • Nuclear Magnetic Resonance, Biomolecular
  • Phospholipids / metabolism
  • Protein Binding
  • Spin Labels
  • Static Electricity
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism*


  • Heparan Sulfate Proteoglycans
  • Lipid Bilayers
  • Multiprotein Complexes
  • Phospholipids
  • Spin Labels
  • TIMP2 protein, human
  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinase 12

Associated data

  • PDB/2MLR
  • PDB/2MLS