The intramolecular agonist is obligate for activation of glycoprotein hormone receptors.
Glycoproteins
/ genetics
HEK293 Cells
Hormones
/ genetics
Humans
Ligands
Membrane Proteins
/ genetics
Mutagenesis
/ genetics
Mutagenesis, Site-Directed
/ methods
Mutation
/ genetics
Peptides
/ genetics
Protein Binding
/ genetics
Protein Domains
/ genetics
Receptors, Thyrotropin
/ genetics
Signal Transduction
/ genetics
G protein-coupled receptors
glycoprotein hormone receptors
hormone receptors
tethered agonist
thyroid-stimulating hormone
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
13
01
2020
revised:
18
06
2020
accepted:
19
06
2020
pubmed:
11
7
2020
medline:
26
2
2021
entrez:
11
7
2020
Statut:
ppublish
Résumé
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 known Tethered Agonistic LIgand (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 how TALI is 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 the TALI region. Here, we report that TALI (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, TALI forms specific interactions between the N-terminus and the transmembrane domain. We show that stabilization of an active state is dependent on TALI, including activation by hormones and constitutively activating mutations.
Identifiants
pubmed: 32648604
doi: 10.1096/fj.202000100R
doi:
Substances chimiques
Glycoproteins
0
Hormones
0
Ligands
0
Membrane Proteins
0
Peptides
0
Receptors, Thyrotropin
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11243-11256Subventions
Organisme : Intramural NIH HHS
ID : Z01 DK011006
Pays : United States
Informations de copyright
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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