title: Evidence of reciprocal reorientation of the catalytic and hemopexin-like domains of full-length MMP-12.
abstract: The proteolytic activity of matrix metalloproteinases toward extracellular matrix components (ECM), cytokines, chemokines, and membrane receptors is crucial for several homeostatic and pathological processes. Active MMPs are a family of single-chain enzymes (23 family members in the human genome), most of which constituted by a catalytic domain and by a hemopexin-like domain connected by a linker. The X-ray structures of MMP-1 and MMP-2 suggest a conserved and well-defined spatial relationship between the two domains. Here we present structural data for MMP-12, suitably stabilized against self-hydrolysis, both in solution (NMR and SAXS) and in the solid state (X-ray), showing that the hemopexin-like and the catalytic domains experience conformational freedom with respect to each other on a time scale shorter than 10(-8) s. Hints on the probable conformations are also obtained. This experimental finding opens new perspectives for the often hypothesized active role of the hemopexin-like domain in the enzymatic activity of MMPs.
authors.affiliation: Magnetic Resonance Center (CERM), University of Florence, Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy. ivanobertini@cerm.unifi.it
authors.forename: Ivano
authors.initials: I
authors.lastname: Bertini
authors.forename: Vito
authors.initials: V
authors.lastname: Calderone
authors.forename: Marco
authors.initials: M
authors.lastname: Fragai
authors.forename: Rahul
authors.initials: R
authors.lastname: Jaiswal
authors.forename: Claudio
authors.initials: C
authors.lastname: Luchinat
authors.forename: Maxime
authors.initials: M
authors.lastname: Melikian
authors.forename: Efstratios
authors.initials: E
authors.lastname: Mylonas
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006466:Hemopexin / Q000737:chemistry*; D053508:Matrix Metalloproteinase 12 / Q000737:chemistry*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation
chemical_list: D006466:Hemopexin; D053508:Matrix Metalloproteinase 12