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Identification of the Peptides That Inhibit the Stimulation of Thyrotropin Receptor by Graves’ Immunoglobulin G from Peptide Libraries¹

Department of Life Science and Biotechnology Research Center, Pohang University of Science and Technology, Pohang; and the Department of Internal Medicine, Seoul National University College of Medicine (C.B.Y.), Seoul, Korea

Address all correspondence and requests for reprints to: Dr. Chi-Bom Chae, Department of Life Science and Biotechnology Research Center, Pohang University of Science and Technology, Pohang 790–784, Korea. E-mail: cbchae{at}vision.postech.ac.kr

Graves’ disease is characterized by the overproduction of thyroid hormones due to the persistent stimulation of TSH receptor by autoantibodies. To determine the epitopes recognized by the autoantibodies, an enzyme-linked immunosorbent assay was developed that uses the human TSH receptor extracellular domain attached to plastic wells. The total IgG from some of the Graves’ patients interacted with the bound TSH receptor (TSHR) at a significantly higher level than that in normal individuals. The IgG preparation that showed the highest binding activity was used for the identification of peptide sequences that prevent binding of Graves’ IgG to TSHR from positional scanning synthetic peptide combinatorial libraries. A hexapeptide mixture, X₁X₂FDDA (X₁ is a mixture of E, M, and Y; X₂ is a mixture of E, H, and T), was found to be effective for inhibiting the binding of Graves’ IgG to the TSHR. Further fractionation of X₁X₂FDDA showed that the following three sequences were highly effective: EEFDDA, ETFDDA, and EHFDDA. The second position of the three peptides did not appear to be important. The peptides also inhibited the cAMP synthesis induced by IgG of four of eight patients with Graves’ disease tested. The synthesis of cAMP by TSH was also inhibited by the peptides to some extent. The peptide sequences most likely mimic a part of the conformational epitopes recognized by at least one class of Graves’ IgG.

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