Publications

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

Saito T, et al., 19(9):1917-1928, Cell Rep, 2017

Endoglin (ENG)/CD105 is an essential type I transmembrane glycoprotein of the vascular endothelium, which plays a critical role in angiogenesis and vascular homeostasis. A mutated ENG exists in the genetic disorder HHT1 and involved in tumor angiogenesis and preeclampsia. It has a high potential to be used as a target in anti-angiogenic cancer therapy. It is important to expand the structural biology knowledge of ENG, and how it interacts with the key ligand bone morphogenetic protein 9 (BMP9). Reported herein are the crystal structures of the ectodomain of human ENG and its complex with human BMP9. Binding affinity of BMP9 to purified ENG constructs and mammalianized maltose binding protein (mMBP) control expressed in HEK293T cells were studied by using Bio-Layer Interferometry (BLI). A Pall ForteBio Octet RED96 instrument equipped with High Precision Streptavidin (SAX) Biosensor probes was used to perform BLI assays. BMP9 was biotinylated and loaded onto SAX biosensors. Subsequently, sensor tips were dipped in biocytin to block any unoccupied binding sites in order to reduce nonspecific binding events. Association and dissociation of each ENG construct were studied over a series of ENG concentrations. kon, koff, and KD values were determined. Collectively, the findings of this investigation provide new insights into the molecular basis of the BMP signaling pathway, thus contributing to the future development of therapeutic interventions.

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