Abstract
G-protein betagamma-subunits (G(betagamma)) are active transmembrane
signalling components. Their function recently has been observed
to be regulated by the cytosolic protein phosducin. We show here
that a small fragment (amino acids 215-232) contained in the C-terminus
of phosducin is sufficient for high-affinity interactions with G(betagamma).
Corresponding peptides not only disrupt G(betagamma)-G(alpha) interactions,
as defined by G(betagamma)-stimulated GTPase activity of alpha(o),
but also other G(betagamma)-mediated functions. The NMR structure
of a peptide encompassing this region shows a loop exposing the side
chains of Glu223 and Tyr224, and peptides with a substitution of
either of these amino acids show a complete loss of activity towards
G(o). Mutation of this Tyr224 to Ala in full-length phosducin reduced
the functional activity of phosducin to that of phosducin's isolated
N-terminus, indicating the importance of this residue within the
short, structurally defined C-terminal segment. This small peptide
derived from phosducin, may represent a model of a G(betagamma) inhibitor,
and illustrates the potential of small compounds to affect G(betagamma)
functions.
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