Structural basis of the human endoglin-BMP9 interaction: Insights into BMP signaling and HHT1

Summary 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.
Graphical Abstract
Highlights • Crystal structures of human ENG and its complex with BMP9 were determined • The orphan domain of ENG adopts a fold that explains the effect of HHT1 mutations • ZP module-mediated dimerization of ENG creates a clamp that secures homodimeric BMP9 • ENG-bound BMP9 can interact with the ALK1 receptor but not the ActRIIB receptor
Endoglin (ENG)/CD105, a key player in angiogenesis and vascular homeostasis, is mutated in the genetic disorder HHT1 and implicated in tumor angiogenesis and preeclampsia. Saito et al. determine structures of human ENG alone and in complex with the physiological ligand BMP9, shedding light onto the molecular basis of BMP signaling.