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    Evolution, Structure and fonction of GPCRs

    Evolution, Structure and fonction of GPCRs

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    Marie Chabbert

     

     

     

     

     

     

     

    Team members : 

    Marie Chabbert, Ph.D.

    Régis Coutant, M.D., Ph.D.

    Patrice Rodien, M.D., Ph.D.

    Claire Briet, M.D., Ph.D.

    Mathilde Munier,  Ph.D, Postdoctoral Fellow

    Louis Gourdin, Technician

    Hélène Ruduelle, Undergraduate student

     

    With about 800 members, the super-family of G-protein-coupled receptors (GPCRs) is involved in most physio-pathological functions and is the target of about a quarter of available drugs. GPCRs play a key role in vascular regulation:

    • directly through receptors of vasoactive peptides (AT1, AT2, BK1, BK2, UR2R, ETA, ETB…) and purinergic receptors (P2YR2, P2YR6)
    • indirectly through the immune response (e.g chemokine receptors), adaptive response to stress (catecholamine receptors) and endocrine regulation of the metabolic control.
    • directly through receptors of vasoactive peptides (AT1, AT2, BK1, BK2, UR2R, ETA, ETB…) and purinergic receptors (P2YR2, P2YR6)
    • indirectly through the immune response (e.g chemokine receptors), adaptative response to stress (catecholamine receptors) and endocrine regulation of the metabolic control.

     

    We are interested in the sequence-structure-function relationships of GPCRs. We aim at deciphering molecular mechanisms of receptor activation and function, with application to drug design. Our approach is based on the analysis of evolutionary information. In particular, we study the evolutionary mechanisms that led to the expansion and diversification of such a large family, in order to understand the specificity of each sub-family.

     

    Previously, using computational approaches (Fig. 1), we have shown that two major pathways of GPCR evolution are related to mutations of or near proline residues (Pelé et al., 2011). A first pathway is related to the deletion of one residue in helix 2, leading to receptors with the P2.58 pattern in transmembrane helix 2 (TM2). By divergent evolution, this pathway led to vasoactive peptide, chemokine and purinergic receptors (Devillé et al., 2009). A second pathway is related to the correlated mutations of proline residues in TM2 and TM5, in several independent sub-families (Pelé et al., 2011).

     


    Figure : The human non-olfactory class A receptors are projected onto the first two dimensions of the sequence space. The color code indicates the proline pattern of TM2 (left) and TM5 (right). The spanning ellipses indicate the receptor clusters corresponding to the P2.58 pattern and to the correlated absence of proline in TM2 and TM5. Adapted from Pelé et al., 2011, Plos One, 6 : 1110.

     

    How these mutations affect receptor activation remains to be determined. To answer this question, we use both computational and molecular biology approaches. Computational approaches are based on multidimensional scaling and correlation analysis of GPCR sequences from cnidarians to humans to determine key residues whose mutation led to emergence of new sub-families and the role of these residues in the activation mechanism. Molecular modelling of receptors of interest relies on our classification of helical distortions into a limited number of conformations with precise structural requirement (Devillé et al., 2008; Rey et al., 2010). Experimentally, we study the relationship between helical reorientation and activation, in particular for the receptors of glycoprotein hormones.

     

    Collaborations:

    - H. Abdi (University of Texas at Dallas),

    - H. Castel (INSERM U982, Rouen),

    - I. Milazzo (CNRS 6014COBRA, Rouen).

     

    Publications

    1. Munier M, Grouleff J, Gourdin L, Fauchard M, Chantreau V, Henrion D, Coutant R, Schiøtt B, Chabbert M, Rodien P. In Vitro Effects of the Endocrine Disruptor p,p'DDT on Human Follitropin Receptor. Environ Health Perspect. 2016 Feb 19. [Epub ahead of print] PMID: 26895433. 

    2. Pelé J., Bécu J.M., Abdi H. and Chabbert M. (2012) Bios2mds: an R package for comparing orthologous protein families by metric multidimensional scaling. BMC Bioinformatics, 13:133.

    3. Chabbert M., Castel H., Pelé J., Devillé J., Legendre R. and Rodien P. (2012) Evolution of class A G-protein-coupled receptors: implications for molecular modeling. Curr. Med. Chem., 19:1110-8.

    4. Pelé J., Abdi H., Moreau M., Thybert D. and Chabbert M. (2011) Multidimensional scalling reveals the main evolutionary pathways of class A G-protein coupled receptors. PLoS One 6(4):e19094.

    5. Rey J., Devillé J., and Chabbert M. (2010) Structural determinants stabilizing helical distortions related to proline. J. Struct. Biol., 171: 266-76.

    6. Rodien P, Beau I, Vasseur C. (2010) Ovarian hyperstimulation syndrome (OHSS) due to mutations in the follicle-stimulating hormone receptor. Ann Endocrinol 71:206-9.

    7. Devillé J., Rey J. and Chabbert M. (2009) An indel in transmembrane helix 2 helps to trace molecular evolution of class A G-protein coupled receptors. J. Mol. Evol., 68: 475-89.

    8. Devillé J., Rey J. and Chabbert M. (2008) Comprehensive analysis of the helix-X-helix motif in soluble proteins. PROTEINS, 72: 115-135.

    9. Royer J, Lefevre-Minisini A, Caltabiano G, Lacombe T, Malthiery Y, Savagner F, Pardo L, Rodien P. (2008) The cloned equine thyrotropin receptor is hypersensitive to human chorionic gonadotropin; identification of three residues in the extracellular domain involved in ligand specificity. Endocrinology. 149:5088-96.