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

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

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Department of Biochemistry, University of Missouri, 117 Schweitzer Hall, Columbia, Missouri 65211, USA.
Molecular Cytology Core, 120 Bond Life Sciences Center, University of Missouri, Columbia, Missouri 65211, USA.
College of Medical and Dental Sciences, School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.


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.

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