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Autoantibody mimicry of hormone action at the thyrotropin receptor.
- Source :
-
Nature [Nature] 2022 Sep; Vol. 609 (7928), pp. 846-853. Date of Electronic Publication: 2022 Aug 08. - Publication Year :
- 2022
-
Abstract
- Thyroid hormones are vital in metabolism, growth and development <superscript>1</superscript> . Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR) <superscript>2</superscript> . In patients with Graves' disease, autoantibodies that activate the TSHR pathologically increase thyroid hormone activity <superscript>3</superscript> . How autoantibodies mimic thyrotropin function remains unclear. Here we determined cryo-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. Thyrotropin selects an upright orientation of the extracellular domain owing to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a patient with Graves' disease selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in the seven-transmembrane-segment domain via a conserved hinge domain, a tethered peptide agonist and a phospholipid that binds within the seven-transmembrane-segment domain. Rotation of the TSHR extracellular domain relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to other G-protein-coupled receptors with large extracellular domains.<br /> (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Cell Membrane metabolism
Graves Disease immunology
Graves Disease metabolism
Humans
Phospholipids metabolism
Protein Domains
Receptors, G-Protein-Coupled agonists
Receptors, G-Protein-Coupled chemistry
Receptors, G-Protein-Coupled ultrastructure
Rotation
Cryoelectron Microscopy
Immunoglobulins, Thyroid-Stimulating chemistry
Immunoglobulins, Thyroid-Stimulating immunology
Immunoglobulins, Thyroid-Stimulating pharmacology
Immunoglobulins, Thyroid-Stimulating ultrastructure
Receptors, Thyrotropin agonists
Receptors, Thyrotropin chemistry
Receptors, Thyrotropin immunology
Receptors, Thyrotropin ultrastructure
Thyrotropin chemistry
Thyrotropin metabolism
Thyrotropin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 609
- Issue :
- 7928
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 35940205
- Full Text :
- https://doi.org/10.1038/s41586-022-05159-1