Molecular basis of lutropin recognition by the mannose/GalNAc-4-SO4 receptor

The circulatory half-life of the glycoprotein hormone lutropin (LH) is prec isely regulated by the mannose (Man)/GalNAc-4-SO4 receptor expressed in hep atic endothelial cells. Rapid clearance from the circulation contributes to the episodic rise and fall of LH levels that is essential for maximal stim ulation of the G protein-coupled LH receptor. We have defined two molecular forms of the Man/GalNAc-4-SO4 receptor that differ in ligand specificity, cell and tissue expression, and function. The form expressed by hepatic end othelial cells binds GalNAc-4-SO4-bearing ligands and regulates hormone cir culatory half-life, whereas the form expressed by macrophages binds Man-bea ring ligands and may play a role in innate immunity. We demonstrate that th e GalNAc-4-SO4-specific form in hepatic endothelial cells is dimeric wherea s the Man-specific form in lung macrophages is monomeric, accounting for th e different ligand specificities of the receptor expressed in these tissues . Two cysteine-rich domains, each of which binds a single GalNAc-4-SO4, are required to form stable complexes with LH. The kinetics of LH binding by t he GalNAc-4-SO4-specific form of the receptor in conjunction with its rate of internalization from the cell surface make it likely that only two of th e four terminal GalNAc-4-SO4 moieties present on native LH are engaged befo re receptor internalization. As a result, the rate of hormone clearance wil l remain constant over a wide range of LH concentrations and will not be se nsitive to variations in the number of terminal GalNAc-4-SO4 moieties as lo ng as two or more are present on multiple oligosaccharides.