The intracellular signal transduction processes activated by the angiotensin AT2 receptor, are atypical for a GPCR and different from the AT1 receptor. Although the classic motifs a GPCR are present in AT2 receptor; it fails to demonstrate classic features of G-protein signalling such as desensitization by phosphorylation, and receptor regulation by internalization. Zhang et al., (2017) [1] report the crystal structures of human AT2 bound to an AT2-selective ligand and to an AT1 /AT2 dual ligand, capturing the receptor in an active-like conformation.
They provide a potential explanations for the poor coupling of AT2 to G proteins and β-arrestins. Helix VIII a very different conformation to other GPCRs; the authors suggest it plays a dual role in the modulation of AT2 function, stabilizing an active like receptor state, while repressing canonical AT2 activity in a self-inhibitory manner by sterically blocking the G protein and β –arrestin binding sites. However, on switching to a membrane-bound conformation, helix VIII can support the recruitment of G proteins and β-arrestins for AT2 signalling. The authors propose helix VIII works as a gatekeeper for either suppression or activation of the receptor depending on its post-translational modifications and interactions with various receptor partners and its environment.
[1] Zhang et al. (2017). Structural basis for selectivity and diversity in angiotensin II receptors. Nature, 544(7650):327-332. [PMID: 28379944]
Comments by Anthony Davenport
guidetopharmacology blog 
Leave a Reply