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Fig. 1-14. Model for activation of the thyrotropin (TSH) receptor by various agonists. Interactions between the extracellular domain and the serpentine domain are implicated in the activation mechanism. The TSH receptor is represented with its extracellular domain containing a concave, hormone-binding structure facing rightwards, and a transmembrane serpentine domain. The basal state of the receptor is characterized by an inhibitory interaction between the extracellular domain and the serpentine domain (indicated by the  (-) green sign). In the absence of agonist, the extracellular domain would function as a tethered inverse agonist of the serpentine domain. Binding of physiological agonists (TSH  , B; thyrostimulin  2  5, C), or stimulating autoantibodies (D) switches the ectodomain from inverse agonist to full agonist of the serpentine domain (indicated by the  (+) red sign). Mutation of the Ser in position 281of the ectodomain has the same effect (yellow dot, E). Other mutations may activate directly the serpentine domain by breaking silencing locks between transmembrane helices (the example of Asp619Gly is illustrated; blue dot, F). The serpentine domain may also be activated, by binding of low molecular chemical agonists directly to transmembrane segments (yellow star, G). The serpentine domain in the basal state is shown as a compact blue structure. The fully activated serpentine domain is shown as relaxed red structures with arrows indicating activation of G  s.