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  • Title: Functional role of the "ionic lock"--an interhelical hydrogen-bond network in family A heptahelical receptors.
    Author: Vogel R, Mahalingam M, Lüdeke S, Huber T, Siebert F, Sakmar TP.
    Journal: J Mol Biol; 2008 Jul 18; 380(4):648-55. PubMed ID: 18554610.
    Abstract:
    Activation of family A G-protein-coupled receptors involves a rearrangement of a conserved interhelical cytoplasmic hydrogen bond network between the E(D)RY motif on transmembrane helix 3 (H3) and residues on H6, which is commonly termed the cytoplasmic "ionic lock." Glu134(3.49) of the E(D)RY motif also forms an intrahelical salt bridge with neighboring Arg135(3.50) in the dark-state crystal structure of rhodopsin. We examined the roles of Glu134(3.49) and Arg135(3.50) on H3 and Glu247(6.30) and Glu249(6.32) on H6 on the activation of rhodopsin using Fourier transform infrared spectroscopy of wild-type and mutant pigments reconstituted into lipid membranes. Activation of rhodopsin is pH-dependent with proton uptake during the transition from the inactive Meta I to the active Meta II state. Glu134(3.49) of the ERY motif is identified as the proton-accepting group, using the Fourier transform infrared protonation signature and the absence of a pH dependence of activation in the E134Q mutant. Neutralization of Arg135(3.50) similarly leads to pH-independent receptor activation, but with structural alterations in the Meta II state. Neutralization of Glu247(6.30) and Glu249(6.32) on H6, which are involved in interhelical interactions with H3 and H7, respectively, led to a shift toward Meta II in the E247Q and E249Q mutants while retaining the pH sensitivity of the equilibrium. Disruption of the interhelical interaction of Glu247(6.30) and Glu249(6.32) on H6 with H3 and H7 plays its role during receptor activation, but neutralization of the intrahelical salt bridge between Glu134(3.49) and Arg135(3.50) is considerably more critical for shifting the photoproduct equilibrium to the active conformation. These conclusions are discussed in the context of recent structural data of the beta(2)-adrenergic receptor.
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