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

Takako Saito (1, 2, 3) , Marcel Bokhove (1, 2) , Romina Croci (1, 2) , Sara Zamora-Caballero (1, 2) , Ling Han (1, 2) , Michelle Letarte (4, 5) , Daniele de Sanctis (6) , Luca Jovine (1, 2)

1 Karolinska Inst, Ctr Innovat Med, S-14183 Huddinge, Sweden
2 Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden
3 Fukushima Med Univ, Sch Med, Inst Biomed Sci, Dept Cell Sci, Fukushima 9601295, Japan
4 Univ Toronto, Dept Immunol, Toronto, ON M5G 0A4, Canada
5 Univ Toronto, Hosp Sick Children, Peter Gilgan Ctr Res & Learning, Mol Med, Toronto, ON M5G 0A4, Canada
6 ESRF - European Synchrotron Radiation Facility

Endoglin (ENG)/CD105 is an essential endothelial cell co-receptor of the transforming growth factor beta (TGF-beta) 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

Domaines: Sciences du Vivant [q-bio]

Takako Saito, Marcel Bokhove, Romina Croci, Sara Zamora-Caballero, Ling Han, et al.. Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1. Cell Reports, 2017, 19 (9), pp.1917-1928. ⟨10.1016/j.celrep.2017.05.011⟩. ⟨hal-01691834⟩