The glycoprotein consists of a homodimer of 180 kDA stabilized by intermolecular disulfide bonds. It has a large extracellular domain of about 561 amino acids, a hydrophobic transmembrane domain and a short cytoplasmic tail domain composed of 45 amino acids. The 260 amino acid region closest to the extracellular membrane is referred to as the ZP domain (or, more correctly, ZP module). The outermost extracellular region is termed as the orphan domain (or, more correctly, orphan region (OR)) and it is the part that binds ligands such as BMP-9.
There are two isoforms of endoglin created by alternative splicing: the long isoform (L-endoglin) and the short isoform (S-endoglin). However, the L-isoform is expressed to a greater extent than the S-isoform. A soluble form of endoglin can be produced by the proteolytic cleaving action of metalloproteinase MMP-14 in the extracellular domain near the membrane. 
It has been found on endothelial cells in all tissues, activated macrophages, activated monocytes, lymphoblasts fibroblasts, and smooth muscle cells. Endoglin was first identified using monoclonal antibody (mAb) 44G4 but more mAbs against endoglin have been discovered, giving more ways to identify it in tissues.
It is suggested that endoglin has 5 potential N-linked glycosylation sites in the N-terminal domain (of which N102 was experimentally observed in the crystal structure of the orphan region ()) and an O-glycan domain near the membrane domain that is rich in Serine and Threonine. The cytoplasmic tail contains a PDZ-binding motif that allows it to bind to PDZ containing proteins and interact with them. It contains an Arginine-Glycine-Aspartic Acid (RGD) tripeptide sequence that enables cellular adhesion, through the binding of integrins or other RGD binding receptors that are present in the extracellular matrix (ECM).  This RGD sequence on endoglin is the first RGD sequence identified on endothelial tissue.
X-ray crystallographic structures of human endoglin () and its complex with ligand BMP-9 () revealed that the orphan region of the protein (residues E26-S337) consists of two domains (OR1 and OR2, corresponding to residues E36-T46 + T200-C330 and residues S47-R199, respectively) with a new fold resulting from gene duplication and circular permutation. The ZP module (residues P338-G581), whose ZP-N and ZP-C moieties (residues T349-L443 and N444-S576, respectively) are closely packed against each other, mediates the homodimerization of endoglin by forming an intermolecular disulfide bond that involves cysteine 516. Together with a second 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. In addition to rationalizing a large number of HHT1 mutations, the crystal structure of endoglin shows that the epitope of anti-ENG monoclonal antibody TRC105 overlaps with the binding site for BMP-9.