Human Lutropin (hLH) and Choriogonadotropin (CG) Are Assembled by Different Pathways: A MODEL OF hLH ASSEMBLY |
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Authors: | Michael P Bernard Win Lin Vladyslav Kholodovych William R Moyle |
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Institution: | From the ‡Department of Obstetrics, Gynecology, and Reproductive Sciences.;the §Office of Information Technology (OIT)/High Performance and Research Computing, and ;the ¶Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Piscataway, New Jersey 08854 |
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Abstract: | The glycoprotein hormones are all structurally related heterodimers consisting of an α-subunit and a ligand-specific β-subunit that confers their unique biological activity. Crystal structures showed how the β-subunit surrounds a part of the α-subunit, and we showed the existence of the two mechanisms responsible for that assembly. In human choriogonadotropin, the β-subunit is folded before the subunits dock, and the α-subunit becomes incorporated into the dimer by a mechanism we termed “threading,” passing between parts of the preassembled β-subunit. Here, we show that the human lutropin β-subunit is not folded completely prior to its interaction with the α-subunit and show that docking of the subunits enables the α-subunit to serve as a chaperone to the β-subunit. Based on data described here, we propose that the α-subunit facilitates formation of the human lutropin β-subunit by two mechanisms. First, the cystine knot of the α-subunit potentiates formation of the β-subunit cystine knot, and second, contacts between α-subunit loop 2 and a hydrophobic tail in the β-subunit facilitate formation of the seatbelt latch disulfide, which stabilizes the heterodimer. The primary influence of the α-subunit was seen when the hydrophobic tail was present or absent, but the secondary mechanism was required only when the hydrophobic tail of the β-subunit was present. During the evolution of human choriogonadotropin, neither of these α-subunit roles was necessary for folding of the β-subunit. The complex mechanism for lutropin assembly may be required to provide an additional control on its positive feedback function in vertebrate reproduction. |
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Keywords: | Glycoprotein Hormones Mutagenesis Protein Chimeras Protein Cross-linking Protein Folding Human Choriogonadotropin Human Follitropin Human Lutropin Human Thyrotropin |
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