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J. Biol. Chem., Vol. 276, Issue 18, 14767-14772, May 4, 2001
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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
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*
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
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.
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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