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Vol. 9, Issue 1, 1-14, January 1998
z Requires
Two Signals
Departments of Cellular and Molecular Pharmacology and Medicine and
the Cardiovascular Research Institute, University of California, San
Francisco, California 94143
Three covalent attachments anchor heterotrimeric G proteins to
cellular membranes: the 
subunits are myristoylated and/or palmitoylated, whereas the 
chain is prenylated. Despite the essential role of these modifications in membrane attachment, it is not
clear how they cooperate to specify G protein localization at the
plasma membrane, where the G protein relays signals from cell surface
receptors to intracellular effector molecules. To explore this
question, we studied the effects of mutations that prevent
myristoylation and/or palmitoylation of an epitope-labeled subunit,
z. Wild-type z (z-WT)
localizes specifically at the plasma membrane. A mutant that
incorporates only myristate is mistargeted to intracellular membranes,
in addition to the plasma membrane, but transduces hormonal signals as
well as does z-WT. Removal of the myristoylation site
produced a mutant z that is located in the cytosol, is
not efficiently palmitoylated, and does not relay the hormonal signal.
Coexpression of 
with this myristoylation defective mutant
transfers it to the plasma membrane, promotes its palmitoylation, and
enables it to transmit hormonal signals. Pulse-chase experiments show
that the palmitate attached to this myristoylation-defective mutant
turns over much more rapidly than does palmitate on
z-WT, and that the rate of turnover is further
accelerated by receptor activation. In contrast, receptor activation
does not increase the slow rate of palmitate turnover on
z-WT. Together these results suggest that myristate and
promote stable association with membranes not only by providing hydrophobicity, but also by stabilizing attachment of palmitate. Moreover, palmitoylation confers on z specific
localization at the plasma membrane.
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