Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1

Abstract

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.

Keywords

• bone morphogenetic protein receptors
• cell surface receptors
• endoglin
• growth differentiation factor 2
• hereditary hemorrhagic telangiectasia
• orphan domain
• protein interaction domains and motifs
• TGF-β superfamily proteins
• x-ray crystallography
• zona pellucida domain