title: Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor.
abstract: Binding of a new thyroid-stimulating human monoclonal autoantibody (MAb) K1-18 to the TSH receptor (TSHR) leucine-rich domain (LRD) was predicted using charge-charge interaction mapping based on unique complementarities between the TSHR in interactions with the thyroid-stimulating human MAb M22 or the thyroid-blocking human MAb K1-70. The interactions of K1-18 with the TSHR LRD were compared with the interactions in the crystal structures of the M22-TSHR LRD and K1-70-TSHR LRD complexes. Furthermore, the predicted position of K1-18 on the TSHR was validated by the effects of TSHR mutations on the stimulating activity of K1-18. A similar approach was adopted for predicting binding of a mouse thyroid-blocking MAb RSR-B2 to the TSHR. K1-18 is predicted to bind to the TSHR LRD in a similar way as TSH and M22. The binding analysis suggests that K1-18 light chain (LC) mimics binding of the TSH-α chain and the heavy chain (HC) mimics binding of the TSH-β chain. By contrast, M22 HC mimics the interactions of TSH-α while M22 LC mimics TSH-β in interactions with the TSHR. The observed interactions in the M22-TSHR LRD and K1-70-TSHR LRD complexes (crystal structures) with TSH-TSHR LRD (comparative model) and K1-18-TSHR LRD (predictive binding) suggest that K1-18 and M22 interactions with the receptor may reflect interaction of thyroid-stimulating autoantibodies in general. Furthermore, K1-70 and RSR-B2 interactions with the TSHR LRD may reflect binding of TSHR-blocking autoantibodies in general. Interactions involving the C-terminal part of the TSHR LRD may be important for receptor activation by autoantibodies.
authors: FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff CF14 5DU, UK.
authors: Ricardo
authors: R
authors: Núñez Miguel
authors: Jane
authors: J
authors: Sanders
authors: Paul
authors: P
authors: Sanders
authors: Stuart
authors: S
authors: Young
authors: Jill
authors: J
authors: Clark
authors: Katarzyna
authors: K
authors: Kabelis
authors: Jane
authors: J
authors: Wilmot
authors: Michele
authors: M
authors: Evans
authors: Emma
authors: E
authors: Roberts
authors: Xiaoling
authors: X
authors: Hu
authors: Jadwiga
authors: J
authors: Furmaniak
authors: Bernard
authors: B
authors: Rees Smith
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001323:Autoantibodies / Q000737:chemistry* / Q000378:metabolism*; D001666:Binding Sites, Antibody; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D011989:Receptors, Thyrotropin; D000242:Cyclic AMP