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This interaction has been explained by a \u201creceptor cross-talk,\u201d mediated via \u03b2-arrestin binding. Here we have examined if this interaction can be mediated via direct receptor contact using modeling and experimental approaches.<\/jats:p>\n               <jats:p>First, we docked a model of the leucine-rich domain of the TSHR ectodomain (ECD) to an available cryo-electron microscopy-based structure of the active-state IGF-1R dimer and demonstrated the stability of the complex using molecular dynamics simulations. We then extended the complex with the full-length TSHR and the transmembrane helices of the IGF1R and a 3000\u2005ns simulation also showed stability of this complex. We then performed coimmunoprecipitation studies with anti-TSHR and anti-IGF-1R antibodies using cells expressing the IGF-1R and the full-length TSHR and also cells that expressed the IGF-1R and only the TSHR-ECD and, therefore, unable to bind \u03b2-arrestin. These studies showed a 360\u2005kD complex protein in the immunoprecipitation, which was present in both the full-length TSHR and the TSHR-ECD-only expressing cells, evidencing a direct interaction of receptors via their ectodomains in the absence of arrestin. Colocalized staining of TSHR and IGF-1R in the TSHR-ECD cells further supported this direct interaction.<\/jats:p>\n               <jats:p>These data showed that the TSHR and IGF-1R can interact directly and in the absence of \u03b2-arrestin binding. Understanding these interactions is important in the pathogenesis of TED and its therapeutic intervention.<\/jats:p>","DOI":"10.1210\/endocr\/bqaf009","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T08:35:07Z","timestamp":1737102907000},"source":"Crossref","is-referenced-by-count":11,"title":["Mechanisms in Thyroid Eye Disease: The TSH Receptor Interacts Directly With the IGF-1 Receptor"],"prefix":"10.1210","volume":"166","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4226-3728","authenticated-orcid":false,"given":"Rauf","family":"Latif","sequence":"first","affiliation":[{"name":"Department of Medicine, Thyroid Research Unit, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]},{"name":"James J. Peters VA Medical Center , New York, NY 10468 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0294-4307","authenticated-orcid":false,"given":"Mihaly","family":"Mezei","sequence":"additional","affiliation":[{"name":"Department of Medicine, Thyroid Research Unit, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]},{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3909-2750","authenticated-orcid":false,"given":"Terry F","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Medicine, Thyroid Research Unit, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]},{"name":"James J. 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