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

• DOI: 10.1074/jbc.m114.579771
• Publication Date: 2014-09-19T02:59:39Z
• Authors: Zhenquan Wei; Richard M. Salmon; Paul D. Upton; Nicholas W. Morrell; Wei Li
• Keywords: Proteolysis

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