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

Rama K Koppisetti1, Yan G Fulcher1, Alexander Jurkevich2

  • 1Department of Biochemistry, University of Missouri, 117 Schweitzer Hall, Columbia, Missouri 65211, USA.

Nature Communications
|November 22, 2014
PubMed

Insights

Matrix metalloproteinases (MMPs) bind directly to cell membranes, influencing tissue remodeling and inflammation. This interaction, even when inhibited, suggests MMP-12

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Matrix metalloproteinases (MMPs) are enzymes crucial for tissue remodeling, inflammation, and disease.
  • The surface activity of some soluble MMPs near cell membranes remains poorly understood.

Purpose of the Study:

  • To investigate the direct binding of Matrix metalloproteinase-12 (MMP-12) to cellular membranes.
  • To elucidate the mechanisms and interfaces involved in MMP-12 membrane association.
  • To explore the implications of MMP-12 membrane binding for its function in innate immunity and inflammation.

Main Methods:

  • Paramagnetic Nuclear Magnetic Resonance (NMR) spectroscopy to study protein-membrane interactions.
  • Fluorescence techniques to visualize MMP-12 binding to lipid bilayers and cellular membranes.
  • Utilizing spin-labeled membrane mimics and vesicles for binding assays.

Main Results:

  • MMP-12 directly binds to lipid bilayers and cellular membranes through distinct interfaces on its catalytic domain.
  • Specific loops with basic and hydrophobic residues mediate contact with the phospholipid bilayer.
  • MMP-12 is rapidly internalized into cells, localizing to perinuclear regions and the nucleus.
  • Tissue inhibitor of metalloproteinase-2 (TIMP-2) binding alters MMP-12's membrane interaction sites but does not abolish binding.

Conclusions:

  • MMP-12 possesses intrinsic membrane-binding capabilities, utilizing multiple interaction sites.
  • The enzyme's ability to associate with cell membranes, including the nuclear envelope, suggests novel roles beyond extracellular matrix degradation.
  • MMP-12's membrane interactions may be critical for targeting its enzymatic activities to modulate innate immune responses and inflammatory processes.

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