Endocrine Abstracts

Graves’ disease (GD) is caused by autoantibodies to the thyrotropin receptor (TSHR) which mimic the action of TSH. Thyroid stimulating antibodies (TSAB) predominantly signal via the cAMP/PKA cascade whilst blocking antibodies (TBAB) prevent TSH binding. Flow cytometry reveals TSHR antibodies which bind the receptor but do not activate cAMP or inhibit TSH binding. These ‘neutral’ antibodies were identified in people with euthyroid Graves’ orbitopathy (GO, eye disease due to remodelling of orbital contents). Studies of murine monoclonal neutral TSHR antibodies revealed the ability to signal via alternative cascades (PKC) and may be relevant to GO pathogenesis. Recent studies using cryo-EM have provided valuable insight into TSHR activation by TSH and TSAB. The TSHR comprises extra-cellular (ECD) and 7 transmembrane domains (7TM) and naturally cleaves into A and B subunits joined by di-sulphide bridges. The ECD in an ‘upright’ position leads to activation, the unliganded receptor can transiently adopt this position, explaining its constitutive activity. TSH and TSAB stabilize an upright ECD because of steric clashes between ligand and membrane bilayer but TBAB maintain the ECD in a downward state. Residue E409 in the p10 peptide of the ECD interact with K660 in the 7TM to stabilize a fully activated receptor, i.e. bound to Gαs. The TSHR hinge region seems unnecessary for activation of Gαs, although many neutral antibodies bind this part. Further studies would be required to determine whether the hinge region is necessary for cascades signalling via Gβγ, Gαq or Gα13. Finally proteins for variant TSHR transcripts (lack the 7TM) have been identified in orbital tissues, demonstrated to bind both TSH and TSAB and thus are capable of modulating signalling via the TSHR.