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Thyrotropin-Luteinizing Hormone/Chorionic Gonadotropin

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Thyrotropin-Luteinizing Hormone/Chorionic Gonadotropin Proc. Natl. Acad. Sci. USA Vol. 88, pp. 902-905, February 1991 Medical Sciences Thyrotropin-luteinizing hormone/chorionic gonadotropin receptor extracellular domain chimeras as probes for thyrotropin receptor function (hormone binding/signal transduction) Yuji NAGAYAMA, HARRY L. WADSWORTH, GREGORIO D. CHAZENBALK, DIEGO Russo, Pui SETO, AND BASIL RAPOPORT Thyroid Molecular Biology Unit, Veterans Administration Medical Center, San Francisco, CA 94121; and the University of California, San Francisco, CA 94143-0534 Communicated by William J. Rutter, November 2, 1990 ABSTRACT To define the sites in the extracellular domain site(s) involved in ligand binding or the region(s) important in of the human thyrotropin (TSH) receptor that are involved in signal transduction. TSH binding and signal transduction we constructed chimeric Recent studies indicate that ligand- and antibody-binding thyrotropin-luteinizing hormone/chorionic gonadotropin sites in folded globular proteins are conformational and may (TSH-LH/CG) receptors. The extracellular domain of the consist of discontinuous regions of the linear amino acid human TSH receptor was divided into five regions that were sequence (13-17). In studies defining ligand-binding sites in replaced, either singly or in various combinations, with ho- native proteins it is therefore important to conserve the mologous regions of the rat LH/CG receptor. The chimeric three-dimensional structure of the protein. The considerable receptors were stably expressed in Chinese hamster ovary cells. (30-50%) homology in the extracellular domains of the gly- The data obtained suggest that the carboxyl region of the coprotein hormone receptors together with the presence of 10 extracellular domain (amino acid residues 261418) and par- conserved extracellular cysteine residues [some ofwhich are ticularly the middle region (residues 171-260) play a role in thought to form disulfide bonds (12)] suggest a similar three- signal transduction. The possibility is also raised of an inter- dimensional structure for the extracellular domains of these action between the amino and carboxyl regions of the extra- receptors and make them ideal candidates for homologous cellular domain in the process of signal transduction. With substitution studies of these regions. For this purpose we respect to hormone binding, substitution of the entire extra- performed homologous substitutions in the extracellular do- cellular domain of the LH/CG receptor for the corresponding main of the human TSH receptor with segments of the rat region ofthe TSH receptor resulted in high-affinity human CG LH/CG receptor. The chimeric TSH-LH/CG receptors con- binding with complete loss of TSH binding. Surprisingly, structed reveal that multiple regions in the middle region and however, there was at least one chimera with a substitution at carboxyl-terminal half (residues 171-418) ofthe extracellular each of the five domains that still retained high-affinity TSH domain are involved in signal transduction. In addition, the binding. Substitution of residues 1-170 of the TSH receptor TSH-binding region is likely to span the entire extracellular with the corresponding region of the LH/CG receptor was domain, with multiple discontinuous contact sites. There associated with the retention of high-affinity TSH binding but appears to be considerable tolerance for alteration in the ligand specificity was lost in that TSH and human CG could hormone-binding region. interact functionally with the receptor. In summary, these studies suggest that the middle region and carboxyl half of the MATERIALS AND METHODS extracellular domain ofthe TSH receptor are involved in signal Construction and Functional Expression of Chimeric TSH- transduction and that the TSH-binding region is likely to span LH/CG Receptor cDNAs. Chimeras were constructed using the entire extracellular domain, with multiple discontinuous five restriction endonuclease sites in the extracellular domain contact sites. of the full-length human TSH receptor cDNA in Bluescript (1) (SnaBI at amino acid 82, Mlu I at amino acid 170, Afi II The human thyrotropin (TSH) receptor (1-3) as well as other at amino acid 260, EcoRV at amino acid 360, and Spe I at pituitary [luteinizing hormone (LH) and follicle-stimulating amino acid 418) and the Sal I site in the multiple cloning site hormone (FSH)] and placental [chorionic gonadotropin (CG)] of the vector. Two of the sites in the TSH receptor cDNA glycoprotein hormone receptors (4-6) belong to a subgroup (SnaBI and Afl II) were preexisting restriction sites. The of the guanine nucleotide (G) regulatory protein-coupled other three sites (Mlu I, EcoRV, and Spe I) were chosen by receptor family with very large extracellular domains. With their uniqueness to the plasmid containing the cDNA and 14 incomplete leucine-rich repeated segments this subgroup's were created by using oligonucleotide-directed mutagenesis receptors are also members of the leucine-rich glycoprotein (Bio-Rad Muta-Gene Phagemid in vitro mutagenesis kit) (18). family (7-11). The unusually large size of the extracellular These new sites created two conservative amino acid sub- domain (418 amino acids) of the TSH receptor (764 amino stitutions (Glu -+ Asp at residue 362 and Ile -- Leu at residue acids), the very large size (28 kDa) ofits specific ligand, TSH, 419). The TSH receptor cDNA with the two conserved amino as well as cross-linking studies (12) make it likely that TSH acid substitutions was excised with EcoRI and subcloned into binds to the extracellular domain of this receptor. Indeed, the expression vector pSV2-NEO-ECE (1). human CG (hCG) binds with high affinity to the extracellular Rat LH/CG receptor cDNA was synthesized by the poly- domain of the LH/CG receptor (6). There have been no merase chain reaction (PCR) (19) using as template -10 ng of studies to localize in these large extracellular domains the Abbreviations: TSH, thyrotropin; LH, luteinizing hormone; CG, The publication costs of this article were defrayed in part by page charge chorionic gonadotropin; hCG, human CG; FSH, follicle-stimulating payment. This article must therefore be hereby marked "advertisement" hormone; CHO, Chinese hamster ovary; PCR, polymerase chain in accordance with 18 U.S.C. §1734 solely to indicate this fact. reaction. 902 Downloaded by guest on September 24, 2021 Medical Sciences: Nagayarna et al. Proc. NatL. Acad. Sci. USA 88 (1991) 903 phage DNA extracted from a rat ovarian library (Clontech) was determined in the presence of 1 ,uM TSH and this value and two oligonucleotides containing the appropriate restric- was subtracted from total binding to yield specific TSH tion sites at their5' ends. These restriction sites were then used binding. hCG binding was determined as for TSH with the for substitution ofthe LH/CG receptor cDNA fragments into exceptions that we used the conditions of Buettner and TSH receptor cDNA from which the corresponding region had Ascoli (23). As ligand we used highly purified hCG (11,000 been deleted using the same restriction enzymes. The nucle- units/mg of protein) radiolabeled with 1251 by the stoichio- otide sequences of the PCR-generated fragments of the rat metric chloramine-T method (24) to a specific activity of 50 LH/CG receptor as well as the ligation sites and adjacent ,uCi/,g of protein. Measurements of the intracellular cAMP nucleotide sequences of the TSH receptor in the chimeric response to hormone stimulation (1 hr at 37°C) were as constructs were determined (20) in full and compared to the described (25). previously published sequence data (1, 4). Only chimeric cDNAs without any amino acid substitutions were chosen. RESULTS The chimeric TSH-LH/CG cDNA was transfected into To conserve the three-dimensional structure of the TSH Chinese hamster ovary (CHO) cells by the calcium-phos- receptor we constructed 11 chimeric human TSH-rat LH/CG phate method (21). Surviving colonies were selected by G418 receptor cDNAs (Fig. 1), which were then stably expressed (400 1g/ml) and pooled for study of their ability to bind to in CHO cells. For chimeric receptor construction we divided TSH and hCG and to respond to TSH and hCG with respect the extracellular domain ofthe human TSH receptor into five to an increase in intracellular cAMP levels. regions by restriction endonuclease sites, three ofwhich sites TSH and hCG Binding and Intracellular cAMP Measure- were introduced by site-directed mutagenesis. One or more ments. TSH-binding studies were performed as described (22) ofthese regions were replaced with the homologous region of with the exception that highly purified bovine TSH (30 the rat LH/CG receptor. Pools ofstably transfected clones of units/mg of protein) was iodinated with 125I to =80 ,uCi/,ug cells were tested for their ability to bind to TSH and hCG and of protein using the Bolton-Hunter reagent (4400 Ci/mmol; to respond to TSH and hCG stimulation in terms of an 1 Ci = 37 GBq; New England Nuclear). In addition, we tested increase in intracellular cAMP levels. competition for 1251-labeled TSH (125I-TSH) binding with The human TSH receptor with two conserved amino acid hCG as well as TSH (Sigma). Nonspecific 125I-TSH binding substitutions (introduced with the three new restriction sites EXTRACELLULAR DOMAIN SnaB Mlu I Afi 11 EcoR V Speel RECEPTOR LRCG TSH A I B I c I D I E RECEPTOR 1 82 170 260 360 4118 SUBSTITUTION TSH-LHR-1 1 -83 TSH-LHR-2 I I 84-171 TSH-LHR-3 I _- I 172-260 TSH-LHR-4 261-316 TSH-LHR-5 I_ 317-367 TSH-LHR-6 I 261-367 TSH-LHR-7 I 172-367 TSH-LHR-8 1-171 TSH-LHR-9 1 -260 1-171, TSH-LHR-10 317-367 TSH-LHR-1 1 1-367 FIG. 1. Schematic representation of chimeric TSH-LH/CG receptor extracellular domains. The 418-amino acid extracellular region of the human TSH receptor (764 amino acids) was divided into five arbitrary domains (A-E) on the basis of the indicated restriction sites.
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