Conjoining of the TSH Receptor With the IGF-1 Receptor With Particular Attention to the Role of β1-Arrestin

The thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor 1 receptor (IGF-1R) have been shown to be involved in the development and perpetuation of thyroid eye disease found in up to 40% of patients with Graves disease-a form of autoimmune hyperthyroidism. While these 2 receptors have been known for many years to interact and exhibit synergy, the exact mechanism and the role of this interaction had not been fully evaluated. Recently, the use of a monoclonal blocking antibody to the IGF-1R has been shown to be an important therapeutic tool in improving the disease in such patients, thus revealing the importance of the IGF-1R in the disease pathogenesis. Since we recently presented direct evidence that the TSHR and IGF-1R bind to form a single complex, it is likely that this conjoining contributes to the enhanced signaling of both receptors. Using molecular dynamics simulations, we have furthered our observation by showing the high strength of their association and also determined that our modeling provides no evidence that β1-arrestin is responsible for bringing the TSHR and IGF-1R together in the cell membrane. We show that it is even difficult to break up the TSHR/IGF-1R complex, and while β1-arrestin does indeed bind well it is not necessary for the conjoining to take place.