Abstract
PurposeThe thyroid-stimulating hormone receptor (TSHR) is the target autoantigen for TSHR-stimulating autoantibodies in Graves’ disease. The TSHR is composed of: a leucine-rich repeat domain (LRD), a hinge region or cleavage domain (CD) and a transmembrane domain (TMD). The binding arrangements between the TSHR LRD and the thyroid-stimulating autoantibody M22 or TSH have become available from the crystal structure of the TSHR LRD–M22 complex and a comparative model of the TSHR LRD in complex with TSH, respectively. However, the mechanism by which the TMD of the TSHR and the other glycoprotein hormone receptors (GPHRs) becomes activated is unknown.MethodsWe have generated comparative models of the structures of the inactive (TMD_In) and active (TMD_Ac) conformations of the TSHR, follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) TMDs. The structures of TMD_Ac and TMD_In were obtained using class A GPCR crystal structures for which fully active and inactive conformations were available.ResultsMost conserved motifs observed in GPCR TMDs are also observed in the amino acid sequences of GPHR TMDs. Furthermore, most GPCR TMD conserved helix distortions are observed in our models of the structures of GPHR TMDs. Analysis of these structures has allowed us to propose a mechanism for activation of GPHR TMDs.ConclusionsInsight into the mechanism of activation of the TSHR by both TSH and TSHR autoantibodies is likely to be useful in the development of new treatments for Graves’ disease.
Highlights
The thyroid-stimulating hormone (TSH) receptor (TSHR) is a class A G protein-coupled receptor (GPCR) and is the target autoantigen in Graves’ disease [1, 2]
Most GPCR transmembrane domain (TMD) conserved helix distortions are observed in our models of the structures of Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users
The thyroid-stimulating hormone receptor (TSHR) TMD extracellular loop 1 (ECL1) is 14 residues long, whereas the lengths of the ECL1 of the templates used for modelling range from five to eight residues
Summary
The thyroid-stimulating hormone (TSH) receptor (TSHR) is a class A G protein-coupled receptor (GPCR) and is the target autoantigen in Graves’ disease [1, 2]. Patients with Graves’ disease develop autoantibodies that bind the extracellular domain (ECD) of the TSHR and activate the receptor. The autoantibodies mimic the action of TSH causing stimulation of thyroid hormone synthesis by thyroid cells, leading to hyperthyroidism in Graves’ disease [1, 2]. GPCRs constitute a large superfamily of integral membrane protein receptors. Since a number of GPCR structures have been solved by experimental methods, published and deposited in the Protein Data Bank (PDB). All GPCR structures share a core of seven membrane-spanning helices.
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