内皮糖蛋白
外域
骨形态发生蛋白
血管生成
细胞生物学
配体(生物化学)
化学
受体
生物
癌症研究
生物化学
基因
川地34
干细胞
作者
Takako Saitô,Marcel Bokhove,Romina Croci,Sara Zamora-Caballero,Ling Han,Michelle Letarte,Daniele de Sanctis,Luca Jovine
出处
期刊:Cell Reports
[Elsevier]
日期:2017-05-01
卷期号:19 (9): 1917-1928
被引量:106
标识
DOI:10.1016/j.celrep.2017.05.011
摘要
Endoglin (ENG)/CD105 is an essential endothelial cell co-receptor of the transforming growth factor β (TGF-β) superfamily, mutated in hereditary hemorrhagic telangiectasia type 1 (HHT1) and involved in tumor angiogenesis and preeclampsia. Here, we present crystal structures of the ectodomain of human ENG and its complex with the ligand bone morphogenetic protein 9 (BMP9). BMP9 interacts with a hydrophobic surface of the N-terminal orphan domain of ENG, which adopts a new duplicated fold generated by circular permutation. The interface involves residues mutated in HHT1 and overlaps with the epitope of tumor-suppressing anti-ENG monoclonal TRC105. The structure of the C-terminal zona pellucida module suggests how two copies of ENG embrace homodimeric BMP9, whose binding is compatible with ligand recognition by type I but not type II receptors. These findings shed light on the molecular basis of the BMP signaling cascade, with implications for future therapeutic interventions in this fundamental pathway.
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