 X-ray crystallographic structures of human endoglin () and its complex with ligand BMP-9 () revealed that the orphan region of the protein consists of two domains (OR1 and OR2) with a new fold resulting from gene duplication and circular permutation.The ZP module, whose ZP-N and ZP-C moieties are closely packed against each other, mediates the homodimerization of endoglin by forming an intermolecular disulfide bond that involves cysteine 516.Together with the aforementioned intermolecular disulfide involving cysteine 582, this generates a molecular clamp that secures the ligand via interaction of two copies of OR1 with the knuckle regions of homodimeric BMP-9.