Functional properties of CXCR4 and CXCR7 homo- and heteromers

Early stage researcher 6 (ESR6) project – Joyce Heuninck
Supervision: Thierry Durroux, Jean-Philippe Pin
Host: CNRS (FR) – Institut de Génomique Fonctionnelle de Montpellier (France) – Team Mouillac and Pin/Prezeau

I- Project proposal:

1. Evaluate the existence and localization of CXCR4 and CXCR7 homo- and heteromers in healthy and tumor tissue.

2. Characterize the CXCR4-CXCR7 heteromerisation interface to modulate it.

3. Analyse signalling properties of CXCR4/CXCR7 heteromers versus mono- and homomers. Methodology:

CXCR4 and CXCR7 receptor oligomerization will be studied on mutant receptor expressed in heterologous expression system in a first step. Results will then validated in healthy and tumor tissues. Various strategies and especially Time-resolved FRET techniques will be used to evidence receptor oligomerization. Receptors will be labelled using SNAP-tag technologies on mutant receptors or with fluorescent ligands or nanobodies for receptor expressed in (patho)physiological context. Pharmacological (binding and coupling) properties will be investigated with time-resolved FRET based assays developed in the lab in collaboration with Cisbio Bioassays. Receptor oligomers trafficking will be investigated with Time-resolved FRET microscopy.

Planned secondments: Cisbio Bioassays (Marcoule, FR) – INSERM (UMR-S 996 – LabEx LERMIT – Clamart, FR)


II- Requirement candidate:

Required diploma: MSc degree in molecular/biomedical Life Sciences, Pharmaceutical Sciences or related Life Science degree.

Required expertise: cell culture, cell-based assays, biochemistry, molecular biology. Recommended expertise: GPCR molecular pharmacology, imaging, FRET/BRET based signalling, radioligand binding.

Key publications:
1. Albizu L, Cottet M, Stoev S, Seyer R, Brabet I, Roux T, Bazin H, Bourrier E, Lamarque L, Breton C, Rives M, Kralikova M, Newman AH, Javitch JA, Trinquet E, Manning M, Pin J-P, Mouillac B, Durroux T (2010) Time-resolved FRET between ligands bound on asymmetric G protein-coupled receptor reveals oligomers in native tissues. Nat Chem Biol 6:587-594.

2. Doumazane E, Scholler P, Fabre L, Zwier JM, Trinquet E, Pin JP, Rondard P (2013) Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors. Proc Natl Acad Sci USA 110:E1416-1425.

3. El Moustaine D, Granier S, Doumazane E, Scholler P, Rahmeh R, Bron P, Mouillac B, Baneres JL, Rondard P, Pin JP (2012) Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling. Proc Natl Acad Sci USA 109:16342-16347.

4. Maurel D, Comps-Agrar L, Brock C, Rives M-L, Bourrier E, Ayoub MA, Bazin H, Tinel N, Durroux T, Prézeau L, Trinquet E, Pin J-P (2008) Cell surface protein-protein interaction analysis with combined time-resolved FRET and snap-tag technologies: application to GPCR oligomerization. Nature Methods 5:561-567.

5. Faklaris O, Cottet M, Falco A, Villier B, Laget M, Zwier JM, Trinquet E, Mouillac B, Pin JP, Durroux T (2015) Multicolor time-resolved Förster resonance energy transfer microscopy reveals the impact of GPCR oligomerization on internalization processes. FASEB J. (in press)

6. Hounsou C, Margathe JF, Oueslati N, Belhocine A, Dupuis E, Thomas C, Mann A, Ilien B, Rognan D, Trinquet E, Hibert M, Pin JP, Bonnet D, Durroux T (2015) Time-Resolved FRET Binding Assay to Investigate Hetero-Oligomer Binding Properties: Proof of Concept with Dopamine D1/D3 Heterodimer. ACS Chem Biol. 10:466-74

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