Understanding the thyrotropin receptor function-structure relationship.

The thyrotropin (TSH) receptor (TSHR) is a key protein in the control of thyroid function and a major thyroid autoantigen. Recently, molecular cloning of the receptor has been carried out and we now review the impact of this work on our understanding of the physiology and pathophysiology of the TSHR. Analysis of recombinant TSHR proteins expressed in prokaryotic and eukaryotic systems has indicated that post-translational processing is important for the formation of active receptors. Studies of TSHR glycosylation have shown that a 'mature' form of the receptor containing mainly complex-type sugar residues is principally involved in TSH and TSHR autoantibody (TRAb) binding. In addition, the processing of the TSHR peptide chain into two subunits observed with native TSHR has been confirmed using recombinant TSHR. However, despite considerable efforts in many laboratories, the binding site(s) for TSH and TRAb on the TSHR have not been well characterized as yet and lessons learned from the discovery of naturally occurring amino acid mutations of the TSHR confirm the complexity of the hormone and autoantibody binding sites. Future progress in producing large amounts of pure TSHR as well as monoclonal TRAbs, followed by crystallographic analysis of TSHR-TSH complexes and TSHR-TRAb complexes, should be helpful in providing a better insight into the relationship between TSHR structure and function.