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A more recent version of this article appeared on April 27, 2001
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Papers In Press, published online ahead of print February 8, 2001
J. Biol. Chem, 10.1074/jbc.M008001200
Submitted on August 31, 2000
Revised on February 7, 2001
Accepted on February 8, 2001

A full biological response to autoantibodies in Graves' disease requires a disulfide-bonded loop in the thyrotropin receptor N-terminus homologous to a laminin EGF-like domain

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

Autoimmune Disease Unit, Cedars-Sinai Medical Center, Los Angeles, CA 90048

Corresponding Author: rapoportb{at}cshs.org

We observed amino acid homology between the cysteine-rich N-terminus of the thyrotropin receptor (TSHR) ectodomain and EGF-like repeats in the laminin g1 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 (C) 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 C41 to be the key residue for receptor expression. Forced pairing of C41 with any one of the three upstream C 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 C41 with C29 or with C31, but not with C24, retained functional activity comparable to the wild-type TSHR. These data suggest that an N-terminal disulfide-bonded loop between C41 and C29 or its close neighbor C31 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 g1 chain EGF-like repeat 11, suggest conformational similarity between the two molecules and raise the possibility of molecular mimicry in the pathogenesis of Graves' disease.


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