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Cell Rep. 2017 May 30;19(9):1917-1928. doi: 10.1016/j.celrep.2017.05.011.

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

Author information

1
Department of Biosciences and Nutrition and Center for Innovative Medicine, Karolinska Institutet, Huddinge 14183, Sweden.
2
Molecular Medicine, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, University of Toronto, Toronto, ON M5G 0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON M5G 0A4, Canada.
3
ESRF-The European Synchrotron, Grenoble 38000, France.
4
Department of Biosciences and Nutrition and Center for Innovative Medicine, Karolinska Institutet, Huddinge 14183, Sweden. Electronic address: luca.jovine@ki.se.

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:

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

PMID:
28564608
PMCID:
PMC5464963
DOI:
10.1016/j.celrep.2017.05.011
[Indexed for MEDLINE]
Free PMC Article

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