title: Extracellular Regulation of Bone Morphogenetic Protein Activity by the Microfibril Component Fibrillin-1.
abstract: Since the discovery of bone morphogenetic proteins (BMPs) as pluripotent cytokines extractable from bone matrix, it has been speculated how targeting of BMPs to the extracellular matrix (ECM) modulates their bioavailability. Understanding these processes is crucial for elucidating pathomechanisms of connective tissue disorders characterized by ECM deficiency and growth factor dysregulation. Here, we provide evidence for a new BMP targeting and sequestration mechanism that is controlled by the ECM molecule fibrillin-1. We present the nanoscale structure of the BMP-7 prodomain-growth factor complex using electron microscopy, small angle x-ray scattering, and circular dichroism spectroscopy, showing that it assumes an open V-like structure when it is bioactive. However, upon binding to fibrillin-1, the BMP-7 complex is rendered into a closed ring shape, which also confers latency to the growth factor, as demonstrated by bioactivity measurements. BMP-7 prodomain variants were used to map the critical epitopes for prodomain-growth factor and prodomain-prodomain binding. Together, these data show that upon prodomain binding to fibrillin-1, the BMP-7 complex undergoes a conformational change, which denies access of BMP receptors to the growth factor.
authors.affiliation: From the Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Street 52, 50931 Cologne, Germany.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Wohl
authors.affiliation: the Wellcome Trust Centre for Cell-Matrix Research and; Faculty of Life Sciences, University of Manchester, Michael Smith Building, Manchester M13 9PT, United Kingdom, and.
authors.forename: Helen
authors.initials: H
authors.lastname: Troilo
authors.affiliation: Faculty of Life Sciences, University of Manchester, Michael Smith Building, Manchester M13 9PT, United Kingdom, and.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Collins
authors.affiliation: the Wellcome Trust Centre for Cell-Matrix Research and; Faculty of Life Sciences, University of Manchester, Michael Smith Building, Manchester M13 9PT, United Kingdom, and.
authors.forename: Clair
authors.initials: C
authors.lastname: Baldock
authors.affiliation: From the Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Street 52, 50931 Cologne, Germany,; the Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Street 21, 50931 Cologne, Germany. Electronic address: gsengle@uni-koeln.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Sengle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002942:Circular Dichroism; D005109:Extracellular Matrix / Q000378:metabolism*; D000071838:Fibrillin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020894:Microfibrils / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D049329:Nanostructures / Q000737:chemistry / Q000648:ultrastructure; D011485:Protein Binding; D011487:Protein Conformation; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D053838:Scattering, Small Angle; D020349:Surface Plasmon Resonance; D014961:X-Ray Diffraction
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D000071838:Fibrillin-1
keywords: bone morphogenetic protein (BMP); electron microscopy (EM); extracellular matrix; fribrillin; growth factor; signal transduction; small-angle X-ray scattering (SAXS)