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

DS Roseman, JU Baenziger - Proceedings of the National …, 2000 - National Acad Sciences
DS Roseman, JU Baenziger
Proceedings of the National Academy of Sciences, 2000National Acad Sciences
The circulatory half-life of the glycoprotein hormone lutropin (LH) is precisely regulated by
the mannose (Man)/GalNAc-4-SO4 receptor expressed in hepatic endothelial cells. Rapid
clearance from the circulation contributes to the episodic rise and fall of LH levels that is
essential for maximal stimulation 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 endothelial cells binds …
The circulatory half-life of the glycoprotein hormone lutropin (LH) is precisely regulated by the mannose (Man)/GalNAc-4-SO4 receptor expressed in hepatic endothelial cells. Rapid clearance from the circulation contributes to the episodic rise and fall of LH levels that is essential for maximal stimulation 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 endothelial cells binds GalNAc-4-SO4-bearing ligands and regulates hormone circulatory half-life, whereas the form expressed by macrophages binds Man-bearing ligands and may play a role in innate immunity. We demonstrate that the GalNAc-4-SO4-specific form in hepatic endothelial cells is dimeric whereas the Man-specific form in lung macrophages is monomeric, accounting for the 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 the 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 the four terminal GalNAc-4-SO4 moieties present on native LH are engaged before receptor internalization. As a result, the rate of hormone clearance will remain constant over a wide range of LH concentrations and will not be sensitive to variations in the number of terminal GalNAc-4-SO4 moieties as long as two or more are present on multiple oligosaccharides.
National Acad Sciences