Legend to figure 1: Structural model of the TSHR with interacting proteins and highlighted positions for gain-of-function mutations. Left: The model shows different parts of the receptor for which homologous structural information is available. The leucine-rich repeat domain (LRRD) and the hinge region are both harboring determinants for hormone (TSH model (surface) based on the FSH structure (82)) and antibody binding. The hinge region (colored pink) structurally links the LRRD with the serpentine domain made of transmembrane helices (H) 1-7 connected by intracellular (I1-3) and extracellular (E1-3) loops. Three cysteine bridges (yellow spheres) between the C-terminal LRRD and the C-terminus of the hinge region are indicated that are required for correct receptor arrangement and function. Wild type positions of constitutively activating mutations are indicated by side-chain representation (red sticks). Right: The known activating mutations (Table 1) are distributed over the entire serpentine portion of the receptor structure with clustering in the central core and specifically in helix 6. In contrast to other glycoprotein-hormone receptors (GPHRs), naturally occurring activating mutations were also identified in the extracellular loops and in the hinge region (Ser281).