Encoding the β-Arrestin Trafficking Fate of Ghrelin Receptor GHSR1a: C-Tail-Independent Molecular Determinants in GPCRs
![Thumbnail](/bitstream/handle/10576/46843/acsptsci.9b00018.pdf.jpg?sequence=3&isAllowed=y)
عرض / فتح
التاريخ
2019المؤلف
Toth, KrisztianNagi, Karim
Slosky, Lauren M.
Rochelle, Lauren
Ray, Caroline
Kaur, Suneet
Shenoy, Sudha K.
Caron, Marc G.
Barak, Larry S.
...show more authors ...show less authors
البيانات الوصفية
عرض كامل للتسجيلةالملخص
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.
المجموعات
- أبحاث الطب [1413 items ]