4.7 Article

The intramolecular agonist is obligate for activation of glycoprotein hormone receptors

Journal

FASEB JOURNAL
Volume 34, Issue 8, Pages 11243-11256

Publisher

WILEY
DOI: 10.1096/fj.202000100R

Keywords

G protein-coupled receptors; glycoprotein hormone receptors; hormone receptors; tethered agonist; thyroid-stimulating hormone

Funding

  1. Deutsche Forschungsgemeinschaft (DFG) [CRC1365-A03, BR 5108/1, CRC1078-B6, CRC1423]
  2. HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Z01 DK011006]

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In contrast to most rhodopsin-like G protein-coupled receptors, the glycoprotein hormone receptors (GPHR) have a large extracellular N-terminus for hormone binding. The hormones do not directly activate the transmembrane domain but mediate their action via a, thus, far only partially knownTetheredAgonisticLIgand (TALI). The existence of such an intramolecular agonist was initially indicated by site-directed mutation studies and activating peptides derived from the extracellular hinge region. It is still unknown precisely howTALIis involved in intramolecular signal transmission. We combined systematic mutagenesis studies at the luteinizing hormone receptor and the thyroid-stimulating hormone receptor (TSHR), stimulation with a drug-like agonist (E2) of the TSHR, and structural homology modeling to unravel the functional and structural properties defining theTALIregion. Here, we report thatTALI(a) is predisposed to constitutively activate GPHR, (b) can by itself rearrange GPHR into a fully active conformation, (c) stabilizes active GPHR conformation, and (d) is not involved in activation of the TSHR by E2. In the active state conformation,TALIforms specific interactions between the N-terminus and the transmembrane domain. We show that stabilization of an active state is dependent onTALI,including activation by hormones and constitutively activating mutations.

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