The Thyrotropin Receptor Structure and Interactions with Autoantibodies

Cryo-EM studies indicate full length human TSH receptor (TSHR) is a monomer consisting of a leucine-rich repeat (LRR) domain (LRD), hinge region (HR) and transmembrane domain (TMD). Receptor autoantibodies (TRAb) bind to the ECD. In the cell membrane, TSHR transitions between inactive and active states involving rotation of the LRD about the HR with the active state LRD further from the membrane. Cryo-EM structures of the TSHR in complex with different human monoclonal autoantibodies provides a detailed understanding of how they interact with the receptor. Stimulating monoclonal autoantibody M22™ binds to the entire LRD (LRR 1-11) concave surface and cannot interact with inactive state receptor as this would result in a clash between antibody and membrane. No clash occurs when M22™ binds the active state and once bound M22™ holds the receptor in the active state, resulting in prolonged activation. K1-18™, a different stimulating monoclonal autoantibody interacts with LRR 1-11 in a similar way to M22™. Blocking type monoclonal autoantibody K1-70™ only interacts with LRR 1-7 positioning itself clear of the cell membrane when interacting with inactive or active receptor states. Once bound, binding of TSH and other TRAb is prevented. Monoclonal autoantibody 5C9™ interacts differently, binding the inactive conformation from LRR 3 to the HR. Its heavy chain CDR3 interacts with the HR locking the receptor in the inactive state causing inhibition of constitutive activity, activating mutations activity and blocking receptor binding by TSH and TRAb. Elucidation of the structure of the TSHR and mechanisms of its activation and inactivation by TRAb is of great importance for the development of new TSHR specific drugs.