The thyrotropin receptor structure and interactions with autoantibodies

Area of Science:

• Structural biology
• Molecular endocrinology
• Immunology

Background:

• The human TSH receptor (TSHR) is a monomer with extracellular leucine-rich repeat (LRR) and transmembrane domains.
• Receptor autoantibodies (TRAb) target the extracellular TSHR domain, influencing receptor activity.
• TSHR cycles between inactive and active states, involving LRD rotation relative to the membrane.

Purpose of the Study:

• To elucidate the structural mechanisms of TSHR activation and inactivation by monoclonal autoantibodies using cryo-electron microscopy (Cryo-EM).
• To understand how different TRAbs interact with TSHR conformations and modulate its function.

Main Methods:

• Cryo-electron microscopy (Cryo-EM) was used to determine the structures of TSHR in complex with various human monoclonal autoantibodies.
• Analysis of antibody-receptor interactions at atomic resolution.

Main Results:

• Stimulating autoantibody M22™ binds the active TSHR conformation, stabilizing it and causing prolonged activation.
• Blocking autoantibody K1-70™ binds the extracellular domain, preventing TSH and TRAb binding.
• Inhibitory autoantibody 5C9™ binds the inactive TSHR, locking it in an inactive state and blocking TSH/TRAb interactions.

Conclusions:

• Structural insights into TSHR-TRAb interactions reveal distinct mechanisms of receptor modulation.
• Understanding these molecular interactions is crucial for designing novel TSHR-targeted therapeutics for autoimmune thyroid diseases.