Endocrine Abstracts (2004) 7 S29

Glycoprotein hormone receptors: from disease to structure and function

G Vassart

IRIBHM, University of Brussels, Belgium.

Glycoprotein hormone receptors (TSHr, LH/CGr, FSHr)are rhodopsin-like G protein-coupled receptors with a large extracellular N-terminal portion containing leucine rich repeats, responsible for hormone recognition and binding. We have relied on spontaneous gain-of-function mutations in both the serpentine and LRR portions of the receptors to further explore the structure-function relationships of this family of receptors.

ECTODOMAIN. From the observation in a family with gestational hyperthyroidism that a point mutation in the ectodomain of the TSHr resulted in its promiscuous stimulation by hCG, we identified the residues responsible for the recognition specificity. Based on a model of the ectdomain constructed on the template on the RNAase inhibitor, it was found that mutation of eight, or two residues, of the TSHr, into their LH/CG, or FSHr counterparts, resulted in constructs with close to nominal sensitivity to hCG or FSH, respectively. This allowed to delineate the surface of the ectodomain responsible for the specific recognition of hCG.

SERPENTINE DOMAIN. Compilation of a panel of activating mutations identified in toxic thyroid adenomas on a model of the serpentine domain of the TSHr elaborated on the template of rhodopsin allowed identification of interactions implicated in the maintenance of the receptor in the inactive state. The key role played by interaction between D633 (in TM6) and N674 (in TM7) was demonstrated by extensive site-directed mutagenesis.

INTERACTIONS BETWEEN ECTO- AND SERPENTINE DOMAINS. Mutation of S281, in the ectodomain of the TSHr triggers strong increase of its basal activity, leading to close to maximal stimulation. Together with the observation that truncated constructs devoid of the ectodomain displayed modest but definite increase in basal activity, this led us to propose a model for activation of glycoprotein hormone receptors in which, upon binding of the hormone, the ectodomain would switch from a tethered inverse agonist to a tethered full agonist of the serpentine domain.

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