Structural elements directing G proteins and β-arrestin interactions with the human melatonin type 2 receptor revealed by natural variants

Bianca Plouffe, Angeliki Karamitri, Tilman Flock, Jonathan M. Gallion, Shane Houston, Carole A. Daly, Amélie Bonnefond, Jean-Luc Guillaume, Christian Le Gouill, Philippe Froguel, Olivier Lichtarge, Xavier Deupi*, Ralf Jockers*, Michel Bouvier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
17 Downloads (Pure)

Abstract

G protein-coupled receptors (GPCRs) can engage distinct subsets of signaling pathways, but the structural determinants of this functional selectivity remain elusive. The naturally occurring genetic variants of GPCRs, selectively affecting different pathways, offer an opportunity to explore this phenomenon. We previously identified 40 coding variants of the MTNR1B gene encoding the melatonin MT2 receptor (MT2). These mutations differently impact the β-arrestin 2 recruitment, ERK activation, cAMP production, and Gαi1 and Gαz activation. In this study, we combined functional clustering and structural modeling to delineate the molecular features controlling the MT2 functional selectivity. Using non-negative matrix factorization, we analyzed the signaling signatures of the 40 MT2 variants yielding eight clusters defined by unique signaling features and localized in distinct domains of MT2. Using computational homology modeling, we describe how specific mutations can selectively affect the subsets of signaling pathways and offer a proof of principle that natural variants can be used to explore and understand the GPCR functional selectivity.

Original languageEnglish
Pages (from-to)89-101
Number of pages13
JournalACS Pharmacology & Translational Science
Volume5
Issue number2
DOIs
Publication statusPublished - 25 Jan 2022

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