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Originally published In Press as doi:10.1074/jbc.M610929200 on January 25, 2007

J. Biol. Chem., Vol. 282, Issue 12, 9053-9062, March 23, 2007
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Bone Morphogenetic Protein 1 Prodomain Specifically Binds and Regulates Signaling by Bone Morphogenetic Proteins 2 and 4*

Reema Jasuja{ddagger}, Gaoxiang Ge§, Nikolas G. Voss, Jamie Lyman-Gingerich, Amanda M. Branam{ddagger}, Francisco J. Pelegri, and Daniel S. Greenspan{ddagger}§||1

From the {ddagger}Program in Molecular and Cellular Pharmacology, §Department of Pathology and Laboratory Medicine, Departments of Genetics and Medical Genetics, and the ||Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706

Highly purified fractions of bone extracts capable of inducing ectopic bone formation have been reported to contain peptides corresponding to the mature active regions of the TGF-beta-like bone morphogenetic proteins (BMPs) 2–7, and to the prodomain region of the metalloproteinase BMP1. Co-purification of BMPs 2–7 with BMP1 prodomain sequences through the multiple biochemical steps used in these previous reports has suggested the possibility of interactions between the BMP1 prodomain and BMPs 2–7. Here we demonstrate that the BMP1 prodomain binds BMPs 2 and 4 with high specificity and with a KD of ~11 nM, in the physiological range. It is further demonstrated that the BMP1 prodomain is capable of modulating signaling by BMPs 2 and 4 in vitro and in vivo, and that endogenous BMP1 prodomain-BMP4 complexes exist in cell culture media and in tissues.


Received for publication, November 27, 2006 , and in revised form, January 12, 2007.

* This work was supported by National Institutes of Health Grants AR47746 and GM71679 (to D. S. G.). 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: Dept. of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Ave., Madison, WI 53706. Tel.: 608-262-4676; Fax: 608-262-6691; E-mail: dsgreens{at}wisc.edu.


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