Details

Autor(en) / Beteiligte

• Toth, Krisztian
• Nagi, Karim
• Slosky, Lauren M
• Rochelle, Lauren
• Ray, Caroline
• Kaur, Suneet
• Shenoy, Sudha K
• Caron, Marc G
• Barak, Larry S

Titel

Encoding the β‑Arrestin Trafficking Fate of Ghrelin Receptor GHSR1a: C‑Tail-Independent Molecular Determinants in GPCRs

Ist Teil von

• ACS pharmacology & translational science, 2019-08, Vol.2 (4), p.230-246

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• G-protein-coupled receptors (GPCRs) can bias signaling through distinct biochemical pathways that originate from G-protein/receptor and β-arrestin/receptor complexes. Receptor conformations supporting β-arrestin engagement depend on multiple receptor determinants. Using ghrelin receptor GHR1a, we demonstrate by bioluminescence resonance energy transfer and fluorescence microscopy a critical role for its second intracellular loop 2 (ICL2) domain in stabilizing β-arrestin/GHSR1a core interactions and determining receptor trafficking fate. We validate our findings in ICL2 gain- and loss-of-function experiments assessing β-arrestin and ubiquitin-dependent internalization of the CC chemokine receptor, CCR1. Like all CC and CXC subfamily chemokine receptors, CCR1 lacks a critical proline residue found in the ICL2 consensus domain of rhodopsin-family GPCRs. Our study indicates that ICL2, C-tail determinants, and the orthosteric binding pocket that regulates β-arrestin/receptor complex stability are sufficient to encode a broad repertoire of the trafficking fates observed for rhodopsin-family GPCRs, suggesting they provide the essential elements for regulating a large fraction of β-arrestin signaling bias.