7t9m › Citations

Autoantibody mimicry of hormone action at the thyrotropin receptor.

Faust B, Billesbølle CB, Suomivuori CM, Singh I, Zhang K, Hoppe N, Pinto AFM, Diedrich JK, Muftuoglu Y, Szkudlinski MW, Saghatelian A, Dror RO, Cheng Y, Manglik A
Nature (2022)
Related entries: 7t9i, 7t9n, 7utz

Cited: 11 times
EuropePMC logo PMID: 35940205

Abstract

Thyroid hormones are vital to metabolism, growth and development1. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR)2. Autoantibodies that activate the TSHR pathologically increase thyroid hormones in Graves' disease3. How autoantibodies mimic TSH function remains unclear. We determined cryogenic-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. TSH selects an upright orientation of the extracellular domain due to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a Graves' disease patient selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in the seven transmembrane domain via a conserved hinge domain, a tethered peptide agonist, and a phospholipid that binds within the seven transmembrane 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.

Articles - 7t9m mentioned but not cited (1)

  1. Autoantibody mimicry of hormone action at the thyrotropin receptor. Faust B, Billesbølle CB, Suomivuori CM, Singh I, Zhang K, Hoppe N, Pinto AFM, Diedrich JK, Muftuoglu Y, Szkudlinski MW, Saghatelian A, Dror RO, Cheng Y, Manglik A. Nature 609 846-853 (2022)


Reviews citing this publication (3)

  1. G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss. Ma X, Guo J, Fu Y, Shen C, Jiang P, Zhang Y, Zhang L, Yu Y, Fan J, Chai R. Front Mol Neurosci 15 1028125 (2022)
  2. Intracellular VHHs to monitor and modulate GPCR signaling. Raynaud P, Gauthier C, Jugnarain V, Jean-Alphonse F, Reiter E, Bruneau G, Crépieux P. Front Endocrinol (Lausanne) 13 1048601 (2022)
  3. Structure, function and drug discovery of GPCR signaling. Cheng L, Xia F, Li Z, Shen C, Yang Z, Hou H, Sun S, Feng Y, Yong X, Tian X, Qin H, Yan W, Shao Z. Mol Biomed 4 46 (2023)

Articles citing this publication (7)

  1. A minority of final stacks yields superior amplitude in single-particle cryo-EM. Zhu J, Zhang Q, Zhang H, Shi Z, Hu M, Bao C. Nat Commun 14 7822 (2023)
  2. Crystal structure of LGR ligand α2/β5 from Caenorhabditis elegans with implications for the evolution of glycoprotein hormones. Gong Z, Wang W, El Omari K, Lebedev AA, Clarke OB, Hendrickson WA. Proc Natl Acad Sci U S A 120 e2218630120 (2023)
  3. Self Fourier shell correlation: properties and application to cryo-ET. Verbeke EJ, Gilles MA, Bendory T, Singer A. Commun Biol 7 101 (2024)
  4. Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor. Duan J, Xu P, Zhang H, Luan X, Yang J, He X, Mao C, Shen DD, Ji Y, Cheng X, Jiang H, Jiang Y, Zhang S, Zhang Y, Xu HE. Nat Commun 14 519 (2023)
  5. Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8. Sun D, Sun Y, Janezic E, Zhou T, Johnson M, Azumaya C, Noreng S, Chiu C, Seki A, Arenzana TL, Nicoludis JM, Shi Y, Wang B, Ho H, Joshi P, Tam C, Payandeh J, Comps-Agrar L, Wang J, Rutz S, Koerber JT, Masureel M. Nat Commun 14 7940 (2023)
  6. The relaxin receptor RXFP1 signals through a mechanism of autoinhibition. Erlandson SC, Rawson S, Osei-Owusu J, Brock KP, Liu X, Paulo JA, Mintseris J, Gygi SP, Marks DS, Cong X, Kruse AC. Nat Chem Biol (2023)
  7. Year in Thyroidology: Basic Science. Dumitrescu A. Thyroid 33 16-20 (2023)


Quick links