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

Area of Science:

• Structural biology
• Molecular and cell biology
• Biochemistry

Background:

• Endoglin (ENG)/CD105 is a key co-receptor for TGF-β superfamily ligands.
• Mutations in ENG cause hereditary hemorrhagic telangiectasia type 1 (HHT1).
• ENG plays roles in tumor angiogenesis and preeclampsia.

Purpose of the Study:

• To determine the crystal structures of human endoglin (ENG) ectodomain and its complex with bone morphogenetic protein 9 (BMP9).
• To elucidate the molecular interactions between ENG and BMP9.
• To understand the structural basis of BMP signaling and its implications for disease.

Main Methods:

• X-ray crystallography
• Protein complex formation
• Structural analysis

Main Results:

• The crystal structure of the ENG ectodomain and its complex with BMP9 were determined.
• BMP9 binds to a hydrophobic surface on the N-terminal orphan domain of ENG, revealing a novel duplicated fold.
• The binding interface involves residues mutated in HHT1 and overlaps with the TRC105 antibody epitope.
• The structure explains how ENG accommodates dimeric BMP9, compatible with type I but not type II receptor binding.

Conclusions:

• The study provides atomic-level insights into the BMP9-ENG interaction.
• Findings illuminate the molecular basis of BMP signaling through ENG.
• The structural data offers a foundation for developing targeted therapies for HHT and other ENG-related conditions.