Targeting of bone morphogenetic protein growth factor complexes to fibrillin

Gerhard Sengle, Noe L. Charbonneau, Robert N. Ono, Takako Sasaki, Jennifer Alvarez, Douglas R. Keene, Hans Peter Bächinger, Lynn Y. Sakai

Research output: Contribution to journalArticle

145 Scopus citations

Abstract

Both latent transforming growth factor-β (TGF-β)-binding proteins fibrillins are components of microfibril networks, and both interact with members of the TGF-β family of growth factors. Interactions between latent TGF-β-binding protein-1 and TGF-β and between fibrillin-1 and bone morphogenetic protein-7 (BMP-7) are mediated by the prodomain of growth factor complexes. To extend this information, investigations were performed to test whether stable complexes are formed by additional selected TGF-β family members. Using velocity sedimentation in sucrose gradients as an assay, complex formation was demonstrated for BMP-7 and growth and differentiation factor-8 (GDF-8), which are known to exist in prodomain/growth factor complexes. Comparison of these results with complex formation by BMP-2, BMP-4 (full-length and shortened propeptides), BMP-10, and GDF-5 allowed us to conclude that all, except for BMP-2 and the short BMP-4 propeptides, formed complexes with their growth factors. Using surface plasmon resonance, binding affinities between fibrillin and all propeptides were determined. Binding studies revealed that the N-terminal end of fibrillin-1 serves as a universal high affinity docking site for the propeptides of BMP-2, -4, -7, and -10 and GDF-5, but not GDF-8, and located the BMP/GDF binding site within the N-terminal domain in fibrillin-1. Rotary shadowing electron microscopy of molecules of BMP-7 complex bound to fibrillin-1 confirmed these findings and also showed that prodomain binding targets the growth factor to fibrillin. Immunolocalization of BMP-4 demonstrated fibrillar staining limited to certain tissues, indicating tissue-specific targeting of BMP-4. These data implicate the fibrillin microfibril network in the extracellular control of BMP signaling and demonstrate differences in how prodomains target their growth factors to the extracellular space.

Original languageEnglish (US)
Pages (from-to)13874-13888
Number of pages15
JournalJournal of Biological Chemistry
Volume283
Issue number20
DOIs
StatePublished - May 16 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Sengle, G., Charbonneau, N. L., Ono, R. N., Sasaki, T., Alvarez, J., Keene, D. R., Bächinger, H. P., & Sakai, L. Y. (2008). Targeting of bone morphogenetic protein growth factor complexes to fibrillin. Journal of Biological Chemistry, 283(20), 13874-13888. https://doi.org/10.1074/jbc.M707820200