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J. Biol. Chem., Vol. 280, Issue 26, 25111-25118, July 1, 2005

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Crystal Structure of BMP-9 and Functional Interactions with Pro-region and Receptors^*

Monica A. Brown¶, Qinghai Zhao¶||, Kent A. Baker, Chethana Naik||, Cecil Chen||, Laurie Pukac||, Mallika Singh||, Tatiana Tsareva||, Yanick Parice||, Angela Mahoney||, Viktor Roschke||, Indra Sanyal||, and Senyon Choe**

From the Structural Biology Laboratory, The Salk Institute, La Jolla, California 92037, Department of Neurosciences, University of California San Diego, La Jolla, California 92093, and ^||Human Genome Sciences Inc., Rockville, Maryland 20850

Bone morphogenetic proteins (BMPs), a subset of the transforming growth factor (TGF)- superfamily, regulate a diverse array of cellular functions during development and in the adult. BMP-9 (also known as growth and differentiation factor (GDF)-2) potently induces osteogenesis and chondrogenesis, has been implicated in the differentiation of cholinergic neurons, and may help regulate glucose metabolism. We have determined the structure of BMP-9 to 2.3 Å and examined the differences between our model and existing crystal structures of other BMPs, both in isolation and in complex with their receptors. TGF- ligands are translated as precursors, with pro-regions that generally dissociate after cleavage from the ligand, but in some cases (including GDF-8 and TGF-1, -2, and -3), the pro-region remains associated after secretion from the cell and inhibits binding of the ligand to its receptor. Although the proregion of BMP-9 remains tightly associated after secretion, we find, in several cell-based assays, that the activities of BMP-9 and BMP-9·pro-region complex were equivalent. Activin receptor-like kinase 1 (ALK-1), an orphan receptor in the TGF- family, was also identified as a potential receptor for BMP-9 based on surface plasmon resonance studies (BIAcore) and the ability of soluble ALK-1 to block the activity of BMP-9·pro-region complex in cell-based assays.

Received for publication, March 25, 2005

The atomic coordinates and structure factors (code 1ZKZ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grant HD13527 and the American Heart Association (to K. A. B.). 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.

^¶ These authors contributed equally to this work.

^** To whom correspondence should be addressed: Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd. La Jolla, CA 92037-1099. Tel.: 858-453-4100; Fax: 858-452-3683; E-mail: choe{at}salk.edu.

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