Background: Human chorionic gonadotropin (hCG) is a placental hormone that stimulates secretion of the pregnancy-sustaining steroid progesterone. It is a member of a family of glycoprotein hormones that are disulfide-rich heterodimers, with a common alpha-chain and distinctive beta-chains specific to their particular G-protein linked receptors.
Results: We have produced recombinant hCG in mammalian cells as the selenomethionyl protein, and have determined its structure (after partial deglycosylation) at 2.6 A resolution from multiwavelength anomalous diffraction (MAD) measurements. Despite only limited sequence similarity (10% identity), the alpha- and beta-subunits of hCG have similar tertiary folds. Each subunit has a cystine-knot motif at its core of extended hairpin loops. There is a very extensive subunit interface featuring two inter-chain beta-sheets and a unique, disulfide-tethered 'arm' from the beta-subunit which 'embraces' the alpha-subunit. The carboxy-terminal peptide of the beta-subunit, which is rich in O-linked sugars, is disordered.
Conclusions: Structural and sequence comparisons indicate an evolutionary homology, albeit remote, between the glycoprotein hormone chains and other cystine-knot proteins, notably platelet-derived growth factor. Segments of the alpha- and beta-chains that have been convincingly implicated in receptor binding by hCG are juxtaposed on one side of the molecule. A glycosylation site implicated in signal transduction but not in binding is also close to the presumed binding site suggesting a possible coupling between ligand binding and signaling. This study with selenomethionyl protein produced in mammalian cells extends the realm of MAD phasing.