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Originally published In Press as doi:10.1074/jbc.M005568200 on July 10, 2000

J. Biol. Chem., Vol. 275, Issue 39, 30264-30271, September 29, 2000
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Activation of the Luteinizing Hormone Receptor Following Substitution of Ser-277 with Selective Hydrophobic Residues in the Ectodomain Hinge Region*

Koji Nakabayashi, Masataka Kudo, Brian KobilkaDagger , and Aaron J. W. Hsueh§

From the Division of Reproductive Biology, Department of Gynecology and Obstetrics and the Dagger  Department of Medicine, Stanford University School of Medicine, Stanford, California 94305-5317

Glycoprotein hormone receptors are G protein-coupled receptors with ligand-binding ectodomains consisting of leucine-rich repeats. The ectodomain is connected by a conserved cysteine-rich hinge region to the seven transmembrane (TM) region. Gain-of-function mutants of luteinizing hormone (LH) and thyroid-stimulating hormone receptors found in patients allowed identification of residues important for receptor activation. Based on constitutively active mutations at Ser-281 in the hinge region of the thyroid-stimulating hormone receptor, we mutated the conserved serine in the LH (S277I) and follicle-stimulating hormone receptors (S273I) and observed increased basal cAMP production and ligand affinity by mutant receptors. For the LH receptor, conversion of Ser-277 to all natural amino acids led to varying degrees of receptor activation. Hydropathy index analysis indicated that substitution of neutral serine with selective nonpolar hydrophobic residues (Leu>Val>Met>Ile) confers constitutive receptor activation whereas serine deletion or substitution with charged Arg, Lys, or Asp led to defective receptor expression. Furthermore, mutation of the angular proline near Ser-273 to flexible Gly also led to receptor activation. The findings suggest the ectodomain of glycoprotein hormone receptors constrain the TM region. Point mutations in the hinge region of these proteins, or ligand binding to these receptors, could cause conformational changes in the TM region that result in Gs activation.

* This study was supported by National Institutes of Health Grant HD-23273.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed. Tel.: 650-725-6802; Fax: 650-725-7102; E-mail: aaron.hsueh@stanford.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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