Autoantibody mimicry of hormone action at the thyrotropin receptor.

Autor: Faust B; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.; Biophysics Graduate Program, University of California, San Francisco, CA, USA., Billesbølle CB; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA., Suomivuori CM; Department of Computer Science, Stanford University, Stanford, CA, USA.; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA., Singh I; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA., Zhang K; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA., Hoppe N; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.; Biophysics Graduate Program, University of California, San Francisco, CA, USA., Pinto AFM; Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA, USA., Diedrich JK; Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA, USA., Muftuoglu Y; Stanford University School of Medicine, Stanford, CA, USA., Szkudlinski MW; Trophogen, Rockville, MD, USA., Saghatelian A; Clayton Foundation Laboratory for Peptide Biology Lab, Salk Institute for Biological Studies, La Jolla, CA, USA., Dror RO; Department of Computer Science, Stanford University, Stanford, CA, USA.; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA., Cheng Y; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA. Yifan.Cheng@ucsf.edu.; Biophysics Graduate Program, University of California, San Francisco, CA, USA. Yifan.Cheng@ucsf.edu.; Howard Hughes Medical Institute, University of California, San Francisco, CA, USA. Yifan.Cheng@ucsf.edu., Manglik A; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA. Aashish.Manglik@ucsf.edu.; Biophysics Graduate Program, University of California, San Francisco, CA, USA. Aashish.Manglik@ucsf.edu.; Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA. Aashish.Manglik@ucsf.edu.; Chan Zuckerberg Biohub, San Francisco, CA, USA. Aashish.Manglik@ucsf.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Sep; Vol. 609 (7928), pp. 846-853. Date of Electronic Publication: 2022 Aug 08.
DOI: 10.1038/s41586-022-05159-1
Abstrakt: Thyroid hormones are vital in metabolism, growth and development 1 . 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 activity 3 . 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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