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Regulation of Bone Morphogenetic Protein 9 (BMP9) by Redox-dependent Proteolysis

DOI: 10.1074/jbc.M114.579771 DOI Help
PMID: 25237187 PMID Help

Authors: Zhenquan Wei (Department of Medicine, University of Cambridge, School of Clinical Medicine) , Richard Salmon (Department of Medicine, University of Cambridge, School of Clinical Medicine) , Paul D. Upton (Department of Medicine, University of Cambridge, School of Clinical Medicine) , Nicholas W. Morrell (Department of Medicine, University of Cambridge, School of Clinical Medicine) , Wei Li (Department of Medicine, University of Cambridge, School of Clinical Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 289 (45) , PAGES 31150 - 31159

State: Published (Approved)
Published: November 2014
Diamond Proposal Number(s): 6641

Open Access Open Access

Abstract: BMP9, a member of the TGF beta superfamily, is a homodimer that forms a signaling complex with two type I and two type II receptors. Signaling through high-affinity activin receptor-like kinase 1 (ALK1) in endothelial cells, circulating BMP9 acts as a vascular quiescence factor, maintaining endothelial homeostasis. BMP9 is also the most potent BMP for inducing osteogenic signaling in mesenchymal stem cells in vitro and promoting bone formation in vivo. This activity requires ALK1, the lower affinity type I receptor ALK2, and higher concentrations of BMP9. In adults, BMP9 is constitutively expressed in hepatocytes and secreted into the circulation. Optimum concentrations of BMP9 are essential to maintain the highly specific endothelial-protective function. Factors regulating BMP9 stability and activity remain unknown. Here, we showed by chromatography and a 1.9 Å crystal structure that stable BMP9 dimers could form either with (D-form) or without (M-form) an intermolecular disulfide bond. Although both forms of BMP9 were capable of binding to the prodomain and ALK1, the M-form demonstrated less sustained induction of Smad1/5/8 phosphorylation. The two forms could be converted into each other by changing the redox potential, and this redox switch caused a major alteration in BMP9 stability. The M-form displayed greater susceptibility to redox-dependent cleavage by proteases present in serum. This study provides a mechanism for the regulation of circulating BMP9 concentrations and may provide new rationales for approaches to modify BMP9 levels for therapeutic purposes.

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Documents:
31150.full.pdf