Identification of residues in human melatonin type 2 receptor involved in signaling selectivity or general signal transmission using natural variants
Abstract
Melatonin is a neurohormone secreted by the pineal gland mainly regulating circadian rhythm and binding to 2 receptors: MT1 and MT2. A recent genome‐wide association studies revealed 40 non‐synonymous polymorphisms of MT2. All these variants are normally expressed at cell surface and 4 of them show loss of melatonin binding. Given that no crystal structure is available yet for MT2 and that variants are well distributed along MT2, we took advantage of these natural variants to delineate structural features controlling MT2 functionality. By monitoring β‐arrestin 2 recruitment, ERK phosphorylation, inhibition of cAMP production, Gαi1 and Gαz activation, we generated 40 signaling signatures and similar profiles were grouped together using non‐negative matrix factorization (NMF). A total of 8 different types of signatures (clusters) were obtained. Each cluster has unique signaling features and is distinctly spatially localized along MT2. While residues important for general signal transmission are located in transmembrane regions, the residues responsible for signal selectivity are almost exclusively localized in intracellular domains. Using computational homology modeling (PDB ID: 4Zwj and 3sn6), we proposed molecular mechanisms underlying general signal transmission but also Gα/β‐arrestin and Gαz/Gαi1 selectivities. Altogether, our findings represent a proof of principle that natural variants of a given receptor can be exploited and used as a platform to learn more about its structural properties.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2018
- Source ID
- 10.1096/fasebj.2018.32.1_supplement.555.9
Entities
People
- Amélie Bonnefond
- Angeliki Karamitri
- Bianca Plouffe
- Christian Le Gouill
- Jean‐luc Guillaume
- Jonathan M. Gallion
- Michel Bouvier
- Olivier Lichtarge
- Philippe Froguel
- Ralf Jockers
- Tilman Flock
- Xavier Deupí
Organizations
- Baylor College of Medicine
- Defense Advanced Research Projects Agency
- Fonds de Recherche du Québec Santé
- Hôpital Cochin
- Institut Pasteur de Lille
- National Institutes of Health
- National Science Foundation
- Paul Scherrer Institute
- Université de Montréal