TSH receptor oligomers associated with the TSH receptor antibody reactome.

The TSH receptor (TSHR) and its many forms are the primary antigens of Graves' disease as evidenced by the presence of TSHR antibodies of differing biological activity. The TSH holoreceptor undergoes complex post-translational changes including cleavage of its ectodomain and oligomer formation. We have previously shown that the TSHR exists in both monomeric and dimeric structures in the thyroid cell membrane and have demonstrated, by modeling, that the transmembrane domains (TMD) can form stable dimeric structures. Based on these earlier simulations of the TSHR-TMD structure and our most recent model of the full-length TSHR we have now built models of full length TSHR multimers with and without TSH ligand in addition to multimers of the extracellular leucine-rich domain (LRD) - the site of TSH and autoantibody binding. Starting from these models we ran molecular dynamics (MD) simulation of the receptor oligomers solvated with water and counterions; the full-length oligomers also were embedded in a DPPC bilayer. The full length TSHR dimer and trimer models stayed in the same relative orientation and distance during 2000 ns (or longer) MD simulation in keeping with our earlier report of TMD dimerization. Simulations were also performed to model oligomers of the LRD alone; we found a trimeric complex to be even more stable than the dimers. These data provide further evidence that different forms of the TSHR add to the complexity of the immune response to this antigen which in patients with autoimmune thyroid disease generate an autoantibody reactome with multiple types of autoantibody to the TSHR.

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