Common structural requirements for heptahelical domain function in class A and class C G protein-coupled receptors.
G protein-coupled receptors (GPCRs) are key players in cell communication. Several classes of such receptors have been identified. Although all GPCRs possess a heptahelical domain directly activating G proteins, important structural and sequence differences within receptors from different classes suggested distinct activation mechanisms. Here we show that highly conserved charged residues likely involved in an interaction network between transmembrane domains (TM) 3 and 6 at the cytoplasmic side of class C GPCRs are critical for activation of the gamma-aminobutyric acid type B receptor. Indeed, the loss of function resulting from the mutation of the conserved lysine residue into aspartate or glutamate in the TM3 of gamma-aminobutyric acid type B(2) can be partly rescued by mutating the conserved acidic residue of TM6 into either lysine or arginine. In addition, mutation of the conserved lysine into an acidic residue leads to a nonfunctional receptor that displays a high agonist affinity. This is reminiscent of a similar ionic network that constitutes a lock stabilizing the inactive state of many class A rhodopsin-like GPCRs. These data reveal that despite their original structure, class C GPCRs share with class A receptors at least some common structural feature controlling G protein activation.
Binet
Virginie
V
Département de Pharmacologie Moléculaire, Institut de Génomique Fonctionnelle, CNRS-UMR 5203, INSERM U661, Universités Montpellier 1 et 2, 34094 Montpellier Cedex 5.
Duthey
Béatrice
B
Lecaillon
Jennifer
J
Vol
Claire
C
Quoyer
Julie
J
Labesse
Gilles
G
Pin
Jean-Philippe
JP
Prézeau
Laurent
L
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000502:physiology*; D018080:Receptors, GABA-B / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry
D007295:Inositol Phosphates; D043562:Receptors, G-Protein-Coupled; D018080:Receptors, GABA-B; D012243:Rhodopsin; D001120:Arginine; D008239:Lysine