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Originally published In Press as doi:10.1074/jbc.M008001200 on February 8, 2001

J. Biol. Chem., Vol. 276, Issue 18, 14767-14772, May 4, 2001
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A Full Biological Response to Autoantibodies in Graves' Disease Requires a Disulfide-bonded Loop in the Thyrotropin Receptor N Terminus Homologous to a Laminin Epidermal Growth Factor-like Domain*

Chun-Rong Chen, Kunihiko Tanaka, Gregorio D. Chazenbalk, Sandra M. McLachlan, and Basil RapoportDagger

From the Autoimmune Disease Unit, Cedars-Sinai Research Institute and School of Medicine, University of California, Los Angeles, California 90048

We observed amino acid homology between the cysteine-rich N terminus of the thyrotropin receptor (TSHR) ectodomain and epidermal growth factor-like repeats in the laminin gamma 1 chain. Thyroid-stimulating autoantibodies (TSAb), the cause of Graves' disease, interact with this region of the TSHR in a manner critically dependent on antigen conformation. We studied the role of the cluster of four cysteine (Cys) residues in this region of the TSHR on the functional response to TSAb in Graves' patients' sera. As a benchmark we also studied TSH binding and action. Removal in various permutations of the four cysteines at TSHR positions 24, 29, 31, and 41 (signal peptide residues are 1-21) revealed Cys41 to be the key residue for receptor expression. Forced pairing of Cys41 with any one of the three upstream Cys residues was necessary for trafficking to the cell surface of a TSHR with high affinity TSH binding similar to the wild-type receptor. However, for a full biological response to TSAb, forced pairing of Cys41 with Cys29 or with Cys31, but not with Cys24, retained functional activity comparable with the wild-type TSHR. These data suggest that an N-terminal disulfide-bonded loop between Cys41 and Cys29 or its close neighbor Cys31 comprises, in part, the highly conformational epitope for TSAb at the critical N terminus of the TSHR. Amino acid homology, as well as cysteine pairing similar to the laminin gamma 1 chain epidermal growth factor-like repeat 11, suggests conformational similarity between the two molecules and raises the possibility of molecular mimicry in the pathogenesis of Graves' disease.

* This work was supported by National Institutes of Health Grant DK19289.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.

Dagger To whom correspondence should be addressed: Cedars-Sinai Medical Center, 8700 Beverly Blvd., Suite B-131, Los Angeles, CA 90048. Tel.: 310-423-0555; Fax: 310-423-0221; E-mail: rapoportb@cshs.org.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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