Autoantibody mimicry of hormone action at the thyrotropin receptor.
Nature
; 609(7928): 846-853, 2022 09.
Article
en En
| MEDLINE
| ID: mdl-35940205
ABSTRACT
Thyroid hormones are vital in metabolism, growth and development1. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR)2. In patients with Graves' disease, autoantibodies that activate the TSHR pathologically increase thyroid hormone activity3. 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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Receptores de Tirotropina
/
Tirotropina
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Inmunoglobulinas Estimulantes de la Tiroides
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Microscopía por Crioelectrón
Límite:
Humans
Idioma:
En
Revista:
Nature
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos