Mechanism of N-terminal modulation of activity at the melanocortin-4 receptor GPCR.
Most of our understanding of G protein-coupled receptor (GPCR) activation has been focused on the direct interaction between diffusible ligands and their seven-transmembrane domains. However, a number of these receptors depend on their extracellular N-terminal domain for ligand recognition and activation. To dissect the molecular interactions underlying both modes of activation at a single receptor, we used the unique properties of the melanocortin-4 receptor (MC4R), a GPCR that shows constitutive activity maintained by its N-terminal domain and is physiologically activated by the peptide α-melanocyte stimulating hormone (αMSH). We find that activation by the N-terminal domain and αMSH relies on different key residues in the transmembrane region. We also demonstrate that agouti-related protein, a physiological antagonist of MC4R, acts as an inverse agonist by inhibiting N terminus-mediated activation, leading to the speculation that a number of constitutively active orphan GPCRs could have physiological inverse agonists as sole regulators.
Department of Medicine, University of California-San Francisco, San Francisco, CA, USA.
Baran A
BA
Ersoy
Leonardo
L
Pardo
Sumei
S
Zhang
Darren A
DA
Thompson
Glenn
G
Millhauser
Cedric
C
Govaerts
Christian
C
Vaisse
D054369:Agouti-Related Protein / Q000378:metabolism; D002462:Cell Membrane; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D010957:Plasmids; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism
D054369:Agouti-Related Protein; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH