Functional Role of the C-Terminal Amphipathic Helix 8 of Olfactory Receptors and Other G Protein-Coupled Receptors

Abstract

G protein-coupled receptors (GPCRs) transduce various extracellular signals, such as neurotransmitters, hormones, light, and odorous chemicals, into intracellular signals via G protein activation during neurological, cardiovascular, sensory and reproductive signaling. Common and unique features of interactions between GPCRs and specific G proteins are important for structure-based design of drugs in order to treat GPCR-related diseases. Atomic resolution structures of GPCR complexes with G proteins have revealed shared and extensive interactions between the conserved DRY motif and other residues in transmembrane domains 3 (TM3), 5 and 6, and the target G protein C-terminal region. However, the initial interactions formed between GPCRs and their specific G proteins remain unclear. Alanine scanning mutagenesis of the murine olfactory receptor S6 (mOR-S6) indicated that the N-terminal acidic residue of helix 8 of mOR-S6 is responsible for initial transient and specific interactions with chimeric Gα15_olf, resulting in a response that is 2.2-fold more rapid and 1.7-fold more robust than the interaction with Gα15. Our mutagenesis analysis indicates that the hydrophobic core buried between helix 8 and TM1–2 of mOR-S6 is important for the activation of both Gα15_olf and Gα15. This review focuses on the functional role of the C-terminal amphipathic helix 8 based on several recent GPCR studies.

A Paradigm for Peptide Hormone-GPCR Analyses

“…GPCRs are all characterized by a 7-helix bundle, yet an additional helix named the 8th helix, located in the C-terminus proximal to the seventh transmembrane domain, has been recognized [ 102 , 171 , 172 , 173 ]. This eighth helix domain (H8) contains signature amino acids that have been implicated in multiple receptor functions from ligand binding to endocytosis.…”

Identifying G protein-coupled receptor dimers from crystal packings

“…In dimers and 13 there are no H8 helices, and this relaxes any restraint that the helix places on subunitsubunit orientation. The connection between the orientation of the subunits and the position of H8 in the interface was made by Baltoumas et al (2016), and the role of H8 in GPCR functioning has been noted (Sato et al, 2016) with a focus on its interactions with other structural elements of its GPCR and on interactions between the GPCR and G proteins. It is also possible that amino-acid sequence differences or physical research papers Acta Cryst.…”

Crystal Structure of CC Chemokine Receptor 2A in Complex with an Orthosteric Antagonist Provides Insights for the Design of Selective Antagonists

“…Although these differences could be due to crystal packing interactions, the different orientations observed suggest a relatively high flexibility of this helix. Helix 8 is reported to play potential roles in GPCR G-protein coupling and activation (Sensoy and Weinstein, 2015), as well as in expression, internalization, phosphorylation, and dimerization (Sato et al, 2016). Nuclear magnetic resonance studies with the b 2 -adrenergic receptor revealed that minor changes in the relative position of helix 8 do not directly contribute to the signaling process , but confirm the relative flexibility.…”