TSH receptor oligomers associated with the TSH receptor antibody reactome
Abstract:
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.