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J. Biol. Chem., Vol. 283, Issue 20, 13874-13888, May 16, 2008

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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, and Lynn Y. Sakai¹

From the Shriners Hospital for Children and Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239

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.

Received for publication, September 18, 2007 , and in revised form, December 28, 2007.

^* This work was supported, in whole or in part, by National Institutes of Health Grants P01 AR049698 and RO1AR46811 (to L. Y. S.). This work was also supported by the Shriners Hospitals for Children (to L. Y. S., D. R. K., and H. P. B.) and by Deutsche Forschungsgemeinschaft Forschungsstipendium SE1115/1-1 (to G. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Shriners Hospital for Children, 3101 SW Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-221-3436; Fax: 503-221-3451; E-mail: lys{at}shcc.org.

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