Molecular basis of lutropin recognition by the mannose/GalNAc-4-S04 receptor

Daniel S. Roseman, Jacques U. Baenziger

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

The circulatory half-life of the glycoprotein hormone lutropin (LH) is precisely regulated by the mannose (Man) GalNAc-A-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-A-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.

Original languageEnglish
Pages (from-to)9949-9954
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number18
DOIs
StatePublished - Aug 29 2000

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