title: Bilayer Membrane Modulation of Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Structure and Proteolytic Activity.
abstract: Cell surface proteolysis is an integral yet poorly understood physiological process. The present study has examined how the pericellular collagenase membrane-type 1 matrix metalloproteinase (MT1-MMP) and membrane-mimicking environments interplay in substrate binding and processing. NMR derived structural models indicate that MT1-MMP transiently associates with bicelles and cells through distinct residues in blades III and IV of its hemopexin-like domain, while binding of collagen-like triple-helices occurs within blades I and II of this domain. Examination of simultaneous membrane interaction and triple-helix binding revealed a possible regulation of proteolysis due to steric effects of the membrane. At bicelle concentrations of 1%, enzymatic activity towards triple-helices was increased 1.5-fold. A single mutation in the putative membrane interaction region of MT1-MMP (Ser466Pro) resulted in lower enzyme activation by bicelles. An initial structural framework has thus been developed to define the role(s) of cell membranes in modulating proteolysis.
authors.affiliation: Giotto Biotech S.R.L., Via Madonna del Piano 6, 50019 Sesto Fiorentino (FI), Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Cerofolini
authors.affiliation: Department of Chemistry &Biochemistry, Florida Atlantic University, 5353 Parkside Drive, Jupiter, FL 33458, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Amar
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307, Dresden, Germany.
authors.forename: Janelle L
authors.initials: JL
authors.lastname: Lauer
authors.affiliation: CERM, University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino (FI), Italy.|Department of Chemistry "U. Schiff", University of Florence, via della Lastruccia 3, 50019, Sesto Fiorentino (FI), Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Martelli
authors.affiliation: CERM, University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino (FI), Italy.|Department of Chemistry "U. Schiff", University of Florence, via della Lastruccia 3, 50019, Sesto Fiorentino (FI), Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fragai
authors.affiliation: CERM, University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino (FI), Italy.|Department of Chemistry "U. Schiff", University of Florence, via della Lastruccia 3, 50019, Sesto Fiorentino (FI), Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Luchinat
authors.affiliation: Department of Chemistry &Biochemistry, Florida Atlantic University, 5353 Parkside Drive, Jupiter, FL 33458, USA.|Department of Chemistry, The Scripps Research Institute/Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.|Departments of Chemistry and Biology, Torrey Pines Institute for Molecular Studies, 33458, Port St. Lucie, FL 34987, USA.
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Fields
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D003094:Collagen / Q000737:chemistry; D004789:Enzyme Activation; D057809:HEK293 Cells; D006466:Hemopexin / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D008051:Lipid Bilayers / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry* / Q000378:metabolism*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D000072417:Protein Domains; D059748:Proteolysis
chemical_list: D008051:Lipid Bilayers; D003094:Collagen; D006466:Hemopexin; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14