Fig. 1

Potential activation of G-protein signalling of aGPCRs by their tethered agonist. a Irreversible dissociation model: In the inactive stage, the Stachel sequence is located as a β-sheet (magenta) within the GAIN domain. Following an adequate signal (e.g., mechanical force or ligand binding) the N-terminal fragment (NTF) is removed. The tethered agonist is exposed and binds to the 7TMD in the form of an α-helix resulting in G-protein activation. Because the NTF dissociates from the CTF, the receptor needs to be internalised and degraded for inactivation and cannot undergo another activation cycle (not shown). β arrestin-mediated as well as β arrestin-independent mechanisms have been described for aGPCR internalisation. b Reversible isomerisation model: In the inactive stage, the Stachel sequence is prebound as an α-helix to the 7TMD in its inactive or partially active conformation. Following receptor activation, the Stachel sequence isomerises into the fully active conformation resulting in G protein-mediated signalling. Because NTF and CTF remain attached, multiple activation cycles are possible and receptor internalisation is not mandatory, but might eventually also occur after receptor activation. The figure was created with BioRender.com