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
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: |
|
| Use Licence: |
This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available
here |
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