4MPL

Crystal structure of BMP9 at 1.90 Angstrom

4MPL の概要

• エントリーDOI: 10.2210/pdb4mpl/pdb
• 分子名称: Growth/differentiation factor 2 (2 entities in total)
• 機能のキーワード: growth factor/cytokine, cytokine
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted : Q9UK05
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12931.85

構造登録者

Li, W.,Morrell, N.W.,Wei, Z. (登録日: 2013-09-13, 公開日: 2014-09-17, 最終更新日: 2024-10-16)

主引用文献

Wei, Z.,Salmon, R.M.,Upton, P.D.,Morrell, N.W.,Li, W.
Regulation of Bone Morphogenetic Protein 9 (BMP9) by Redox-dependent Proteolysis.
J.Biol.Chem., 289:31150-31159, 2014

PubMed Abstract: BMP9, a member of the TGFβ 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.

PubMed: 25237187
DOI: 10.1074/jbc.M114.579771

実験手法

X-RAY DIFFRACTION (1.9 Å)