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    The melanocortin 4 receptor: Oligomer formation, interaction sites and functional significance


    Chapman, Kathryn L. and Findlay, John B. C. (2013) The melanocortin 4 receptor: Oligomer formation, interaction sites and functional significance. Biochimica et Biophysica Acta, 1828. pp. 535-542. ISSN 0005-2736

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    Official URL: http://dx.doi.org/10.1016/j.bbamem.2012.10.011


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    Abstract

    This study involves the structural and functional properties of the recombinant melanocortin 4 receptor (MC4R) expressed in the HEK-293 cell line. Using co-immuno-purification approaches, the receptor appears to be an oligomer, which can be crosslinked through disulphide bonds involving a native cysteine residue (84) to give a dimeric species. This position is located near the cytosolic region of transmembrane segment 2 and it is suggested that this is an interacting interface between MC4R monomers. Using co-expression of the native protein and a C84A mutant, it appears that the receptor also forms higher order oligomers via alternative interfaces. Interestingly, disulphide crosslink formation does not occur if the receptor is uncoupled from its G-protein, even though the oligomeric state is preserved. This suggests that the conformational changes, which occur on activation, affect the TM2 interface. The pharmacology of the agonist, NDP-MSH, indicates that the MC4R retains high affinity for the ligand in the absence of the G-protein but occupancy for the ligand is increased. The data can be interpreted to suggest that the G-protein exerts a negative allosteric effect on the receptor. Co-expression of one receptor lacking the ability to signal with another, which cannot bind the agonist, restored ligand-dependent activation of the G-protein to situations in which neither receptor on its own could activate the G-protein. Such transactivation suggests meaningful cross talk between the receptor subunits in the oligomeric complex. These studies demonstrate further unique features of the MC4R.

    Item Type: Article
    Additional Information: The definitive published version of this article is available at DOI: 10.1016/j.bbamem.2012.10.011
    Keywords: Melanocortin 4 receptor; Oligomerization; Trans-activation; GPCR;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 6854
    Identification Number: https://doi.org/10.1016/j.bbamem.2012.10.011
    Depositing User: Professor John Findlay
    Date Deposited: 19 Jan 2016 14:52
    Journal or Publication Title: Biochimica et Biophysica Acta
    Publisher: Elsevier
    Refereed: Yes
    Funders: Wellcome Trust
    URI:

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