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J Biol Chem, Vol. 274, Issue 22, 15757-15765, May 28, 1999
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From the Hormones and sensory stimuli activate serpentine
receptors, transmembrane switches that relay signals to heterotrimeric
guanine nucleotide-binding proteins (G proteins). To understand the
switch mechanism, we subjected 93 amino acids in transmembrane helices III, V, VI, and VII of the human chemoattractant C5a receptor to random
saturation mutagenesis. A yeast selection identified 121 functioning
mutant receptors, containing a total of 523 amino acid substitutions.
Conserved hydrophobic residues are located on helix surfaces that face
other helices in a modeled seven-helix bundle (Baldwin, J. M.,
Schertler, G. F., and Unger, V. M. (1997) J. Mol.
Biol. 272, 144-164), whereas surfaces predicted to contact the
surrounding lipid tolerate many substitutions. Our analysis identified
25 amino acid positions resistant to nonconservative substitutions.
These appear to comprise two distinct components of the receptor
switch, a surface at or near the extracellular membrane interface and a
core cluster in the cytoplasmic half of the bundle. Twenty-one of the
121 mutant receptors exhibit constitutive activity. Amino acids
substitutions in these activated receptors predominate in helices III
and VI; other activating mutations truncate the receptor near the
extracellular end of helix VI. These results identify key elements of a
general mechanism for the serpentine receptor switch.
Department of Cellular and Molecular
Pharmacology, University of California, San Francisco, California
94143 and ** Cadus Pharmaceutical Corporation, Tarrytown, New York
10591-6705
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