structural and functional insights into endoglin ligand recognition and binding结构和功能的见解endoglin配体识别和绑定.pdf

Structural and Functional Insights into Endoglin Ligand Recognition and Binding 1 1 1,3 2,3 2,3 Aaron Alt , Laura Miguel-Romero , Jordi Donderis , Mikel Aristorena , Francisco J. Blanco , Adam Round4, Vicente Rubio1,3, Carmelo Bernabeu2,3, Alberto Marina1,3* ´ ´ 1 Instituto de Biomedicina de Valencia, Valencia, Spain, 2 Centro de Investigaciones Biologicas, Madrid, Spain, 3 Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Valencia, Spain, 4 European Molecular Biology Laboratory, Grenoble, France Abstract Endoglin, a type I membrane glycoprotein expressed as a disulfide-linked homodimer on human vascular endothelial cells, is a component of the transforming growth factor (TGF)-b receptor complex and is implicated in a dominant vascular dysplasia known as hereditary hemorrhagic telangiectasia as well as in preeclampsia. It interacts with the type I TGF-b signaling receptor activin receptor-like kinase (ALK)1 and modulates cellular responses to Bone Morphogenetic Protein (BMP)-9 and BMP-10. Structurally, besides carrying a zona pellucida (ZP) domain, endoglin contains at its N-terminal extracellular region a domain of unknown function and without homology to any other known protein, therefore called the orphan domain (OD). In this study, we have determined the recognition and binding ability of full length ALK1, endoglin and constructs encompassing the OD to BMP-9 using combined methods, consisting of surface plasm