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Vol. 9, Issue 4, 885-899, April 1998
Department of Cell Biology and Physiology, Washington University
School of Medicine, St. Louis, Missouri 63110
We have addressed the mechanisms governing the activation and
trafficking of G protein-coupled receptors (GPCRs) by analyzing constitutively active mating pheromone receptors (Ste2p and Ste3p) of
the yeast Saccharomyces cerevisiae. Substitution of the
highly conserved proline residue in transmembrane segment VI of these receptors causes constitutive signaling. This proline residue may
facilitate folding of GPCRs into native, inactive conformations, and/or
mediate agonist-induced structural changes leading to G protein
activation. Constitutive signaling by mutant receptors is suppressed
upon coexpression with wild-type, but not G protein coupling-defective,
receptors. Wild-type receptors may therefore sequester a limiting pool
of G proteins; this apparent "precoupling" of receptors and G
proteins could facilitate signal production at sites where cell surface
projections form during mating partner discrimination. Finally, rather
than being expressed mainly at the cell surface, constitutively active
pheromone receptors accumulate in post-endoplasmic reticulum
compartments. This is in contrast to other defective membrane proteins,
which apparently are targeted by default to the vacuole. We suggest
that the quality-control mechanism that retains receptors in
post-endoplasmic reticulum compartments may normally allow wild-type
receptors to fold into their native, fully inactive conformations
before reaching the cell surface. This may ensure that receptors do not
trigger a response in the absence of agonist.
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