Conjoining of the TSH receptor with the IGF-1 receptor with particular attention to the role of β1 arrestin
Abstract:
The TSH receptor (TSHR) and the IGF-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 two 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.