Molecular basis of lutropin recognition by the mannose/GalNAc-4-SO4 receptor.
The circulatory half-life of the glycoprotein hormone lutropin (LH) is precisely regulated by the mannose (Man)/GalNAc-4-SO(4) 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-SO(4) receptor that differ in ligand specificity, cell and tissue expression, and function. The form expressed by hepatic endothelial cells binds GalNAc-4-SO(4)-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-SO(4)-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-SO(4), are required to form stable complexes with LH. The kinetics of LH binding by the GalNAc-4-SO(4)-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-SO(4) 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-SO(4) moieties as long as two or more are present on multiple oligosaccharides.
Roseman
D S
DS
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Baenziger
J U
JU
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D019281:Dimerization; D004727:Endothelium / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000737:chemistry* / Q000378:metabolism*; D037241:Mannose-Binding Lectins; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D011974:Receptors, LH / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D020349:Surface Plasmon Resonance; D014162:Transfection
D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011974:Receptors, LH; D011993:Recombinant Fusion Proteins; C429528:mannose N-acetylgalactosamine-4-sulfate receptor; D007986:Luteinizing Hormone