Activities per year
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 b-arrestin 2 recruitment, ERK phosphorylation, inhibition of cAMP production, Gi1 and Gz 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 G/b-arrestin and Gz/Gi1 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.
Original language | English |
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Publication status | Published - Apr 2018 |
Externally published | Yes |
Event | Experimental Biology 2018 (USA) - San Diego, United States Duration: 21 Apr 2018 → 25 May 2018 |
Conference
Conference | Experimental Biology 2018 (USA) |
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Country/Territory | United States |
City | San Diego |
Period | 21/04/2018 → 25/05/2018 |
Fingerprint
Dive into the research topics of 'Identification of residues in human melatonin type 2 receptor involved in signaling selectivity or general signal transmission using natural variants'. Together they form a unique fingerprint.Activities
- 1 Participation in conference
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Experimental Biology 2018 (USA)
Plouffe, B. (Participant)
21 Apr 2018 → 25 Apr 2018Activity: Participating in or organising an event types › Participation in conference
Prizes
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Travel Award from the Institute for Research in Immunology and Cancer (Canada) ($1000)
Plouffe, B. (Recipient), 01 Jun 2017
Prize: Prize (including medals and awards)