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Triple-color FRET analysis reveals conformational changes in the WIP-WASp actin-regulating complex.
[wiskott-aldrich syndrome]
Wiskott-
Aldrich
syndrome
protein
(
WASp
)
is
a
key
regulator
of
the
actin
cytoskeletal
machinery
.
Binding
of
WASp-interacting
protein
(
WIP
)
to
WASp
modulates
WASp
activity
and
protects
it
from
degradation
.
Formation
of
the
WIP-WASp
complex
is
crucial
for
the
adaptive
immune
response
.
We
found
that
WIP
and
WASp
interacted
in
cells
through
two
distinct
molecular
interfaces
.
One
interaction
occurred
between
the
WASp-homology-
1
(
WH
1
)
domain
of
WASp
and
the
carboxyl-terminal
domain
of
WIP
that
depended
on
the
phosphorylation
status
of
WIP
,
which
is
phosphorylated
by
protein
kinase
C
θ
(
PKC
θ
)
in
response
to
T
cell
receptor
activation
.
The
other
interaction
occurred
between
the
verprolin
homology
,
central
hydrophobic
region
,
and
acidic
region
(
VCA
)
domain
of
WASp
and
the
amino-terminal
domain
of
WIP
.
This
latter
interaction
required
actin
,
because
it
was
inhibited
by
latrunculin
A
,
which
sequesters
actin
monomers
.
With
triple-color
fluorescence
resonance
energy
transfer
(
3
FRET
)
technology
,
we
demonstrated
that
the
WASp
activation
mechanism
involved
dissociation
of
the
first
interaction
,
while
leaving
the
second
interaction
intact
.
This
conformation
exposed
the
ubiquitylation
site
on
WASp
,
leading
to
degradation
of
WASp
.
Together
,
these
data
suggest
that
the
activation
and
degradation
of
WASp
are
delicately
balanced
and
depend
on
the
phosphorylation
state
of
WIP
.
Our
molecular
analysis
of
the
WIP-WASp
interaction
provides
insight
into
the
regulation
of
actin-dependent
processes
.
