Endocrine Abstracts

The dichotomy between hormone recognition, by the ectodomain containing leucine-rich repeats (LRR), and activation of the G protein, by the rhodopsin-like serpentine portion, is a well established property of glycoprotein hormone receptors (GpHRs). Extensive site-directed mutagenesis experiments and direct structural data have fully confirmed that high affinity recognition of the hormones by their receptors was built within the structure of the LRRs. It is possible to transform a TSH receptor (displaying minimal sensitivity to hCG) into a fully hCG responsive receptor by introducing only 8 aminoacid substitutions at selected positions in TSHr ectodomain. The ectodomain is also the target of the stimulating autoantibodies of Graves’ disease, and epitopes recognized by monoclonal antibodies with stimulating activity have recently been delineated precisely. The question remains as how binding of the hormone or antibodies to the ectodomain results in transduction of the activation signal to the G protein.

The serpentine portions of GpHRs share many structural and functional characteristics with other rhodopsin-like GPCRs. Upon mutation of specific residues in the transmembrane helices, or in the connecting loops, they may display increase in basal activity. In the case of the TSH receptor, such mutations are responsible for hereditary, congenital, or acquired hypothyroidism.

The monomeric model of rhodopsin-like G protein-coupled receptors has progressively yielded the floor to the concept of GPCR being oligo(di)mers, but the functional correlates of dimerization remain unclear. We have shown the existence of homodimers of glycoprotein hormone receptors in living cells, by a combination of biophysical, functional and biochemical approaches. Heterologous binding-competition studies and tracer dissociation experiments demonstrated the existence of strong negative cooperativity of hormone binding in the TSHr and other GpHrs. Together with similar results observed with chemokine and other rhodopsin-like receptors, these data identify allostery as an important functional correlate of GPCRs dimerization.