Extracellular Regulation of Bone Morphogenetic Protein Activity by the Microfibril Component Fibrillin-1

• Published in: The Journal of biological chemistry 2016-06, Vol.291 (24), p.12732-12746
• Main Authors: Wohl, Alexander P., Troilo, Helen, Collins, Richard F., Baldock, Clair, Sengle, Gerhard
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; bone morphogenetic protein (BMP); Bone Morphogenetic Protein 7 - chemistry; Bone Morphogenetic Protein 7 - genetics; Bone Morphogenetic Protein 7 - metabolism; Cell Line; Circular Dichroism; electron microscopy (EM); extracellular matrix; Extracellular Matrix - metabolism; Fibrillin-1 - chemistry; Fibrillin-1 - genetics; Fibrillin-1 - metabolism; fribrillin; Glycobiology and Extracellular Matrices; growth factor; HEK293 Cells; Humans; Microfibrils - metabolism; Microscopy, Electron, Transmission; Models, Molecular; Nanostructures - chemistry; Nanostructures - ultrastructure; Protein Binding; Protein Conformation; Protein Domains; Protein Structure, Secondary; Scattering, Small Angle; signal transduction; small-angle X-ray scattering (SAXS); Surface Plasmon Resonance; X-Ray Diffraction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.704734

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.