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J Biol Chem, Vol. 274, Issue 24, 17033-17041, June 11, 1999
From the The seven transmembrane helices of
serpentine receptors comprise a conserved switch that relays signals
from extracellular stimuli to heterotrimeric G proteins on the
cytoplasmic face of the membrane. By substituting histidines for
residues at the cytoplasmic ends of helices III and VI in retinal
rhodopsin, we engineered a metal-binding site whose occupancy by Zn(II)
prevented the receptor from activating a retinal G protein,
Gt (Sheikh, S. P., Zvyaga, T. A.,
Lichtarge, O., Sakmar, T. P., and Bourne, H. R. (1996) Nature 383, 347-350). Now we report engineering of
metal-binding sites bridging the cytoplasmic ends of these two helices
in two other serpentine receptors, the
Similar Structures and Shared Switch Mechanisms of the
2-Adrenoceptor and the Parathyroid Hormone Receptor
Zn(II) BRIDGES BETWEEN HELICES III AND VI BLOCK
ACTIVATION
,,,
Department of Cellular and
Molecular Pharmacology and the ¶ Endocrine Unit, Department of
Veterans Affairs, University of California, San
Francisco, California 94143
2-adrenoreceptor
and the parathyroid hormone receptor; occupancy of the metal-binding
site by Zn(II) markedly impairs the ability of each receptor to mediate
ligand-dependent activation of Gs, the
stimulatory regulator of adenylyl cyclase. We infer that these two
receptors share with rhodopsin a common three-dimensional architecture
and an activation switch that requires movement, relative to one
another, of helices III and VI; these inferences are surprising in the
case of the parathyroid hormone receptor, a receptor that contains
seven stretches of hydrophobic sequence but whose amino acid sequence
otherwise shows no apparent similarity to those of receptors in the
rhodopsin family. These findings highlight the evolutionary
conservation of the switch mechanism of serpentine receptors and help
to constrain models of how the switch works.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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