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

Rama K. Koppisetti, Yan G. Fulcher, Alexander Jurkevich, Stephen H. Prior, Jia Xu, Marc Lenoir, Michael Overduin and Steven R. Van Doren ()
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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

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6552

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