Journal
CELL REPORTS
Volume 19, Issue 9, Pages 1917-1928Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.05.011
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Funding
- Karolinska Institutet
- Center for Innovative Medicine, Swedish Research Council [2012-5093]
- Goran Gustafsson Foundation
- Sven and Ebba-Christina Hagberg Foundation
- an EMBO Young Investigator award
- European Research Council (ERC) [260759]
- BioStruct-X [283570]
- European Research Council (ERC) [260759] Funding Source: European Research Council (ERC)
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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.
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