TSH Receptor Oligomers Associated With the TSH Receptor Antibody Reactome.

Autor:	Mezei M; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, 10019, New York, USA.; Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, 10019, New York, USA., Latif R; Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, 10019, New York, USA.; Thyroid Research Unit, James J. Peters VA Medical Center, New York, 10019, New York, USA., Davies TF; Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, 10019, New York, USA.; Thyroid Research Unit, James J. Peters VA Medical Center, New York, 10019, New York, USA.
Jazyk:	angličtina
Zdroj:	Endocrinology [Endocrinology] 2024 Aug 27; Vol. 165 (10).
DOI:	10.1210/endocr/bqae099
Abstrakt:	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 posttranslational 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, the site of TSH and autoantibody binding. Starting from these models we ran molecular dynamics simulations of the receptor oligomers solvated with water and counterions; the full-length oligomers also were embedded in a dipalmitoylphosphatidylcholine bilayer. The full-length TSHR dimer and trimer models stayed in the same relative orientation and distance during 2000 ns (or longer) molecular dynamics simulation in keeping with our earlier report of TMD dimerization. Simulations were also performed to model oligomers of the leucine-rich domain 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 that, in patients with autoimmune thyroid disease, generate an autoantibody reactome with multiple types of autoantibody to the TSHR. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu