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Structure-function analysis of peroxisomal ATP-binding cassette transporters using chimeric dimers.
[x-linked adrenoleukodystrophy]
ABCD
1
and
ABCD
2
are
two
closely
related
ATP-binding
cassette
half
-transporters
predicted
to
homodimerize
and
form
peroxisomal
importers
for
fatty
acyl-
CoAs
.
Available
evidence
has
shown
that
ABCD
1
and
ABCD
2
display
a
distinct
but
overlapping
substrate
specificity
,
although
much
remains
to
be
learned
in
this
respect
as
well
as
in
their
capability
to
form
functional
heterodimers
.
Using
a
cell
model
expressing
an
ABCD
2
-
EGFP
fusion
protein
,
we
first
demonstrated
by
proximity
ligation
assay
and
co
-immunoprecipitation
assay
that
ABCD
1
interacts
with
ABCD
2
.
Next
,
we
tested
in
the
pxa
1
/
pxa
2
Δ
yeast
mutant
the
functionality
of
ABCD
1
/
ABCD
2
dimers
by
expressing
chimeric
proteins
mimicking
homo-
or
heterodimers
.
For
further
structure-function
analysis
of
ABCD
1
/
ABCD
2
dimers
,
we
expressed
chimeric
dimers
fused
to
enhanced
GFP
in
human
skin
fibroblasts
of
X-
linked
adrenoleukodystrophy
patients
.
These
cells
are
devoid
of
ABCD
1
and
accumulate
very
long
-chain
fatty
acids
(
C
2
6
:
0
and
C
2
6
:
1
)
.
We
checked
that
the
chimeric
proteins
were
correctly
expressed
and
targeted
to
the
peroxisomes
.
Very
long
-chain
fatty
acid
levels
were
partially
restored
in
transfected
X-
linked
adrenoleukodystrophy
fibroblasts
regardless
of
the
chimeric
construct
used
,
thus
demonstrating
functionality
of
both
homo-
and
heterodimers
.
Interestingly
,
the
level
of
C
2
4
:
6
n-
3
,
the
immediate
precursor
of
docosahexaenoic
acid
,
was
decreased
in
cells
expressing
chimeric
proteins
containing
at
least
one
ABCD
2
moiety
.
Our
data
demonstrate
for
the
first
time
that
both
homo-
and
heterodimers
of
ABCD
1
and
ABCD
2
are
functionally
active
.
Interestingly
,
the
role
of
ABCD
2
(
in
homo-
and
heterodimeric
forms
)
in
the
metabolism
of
polyunsaturated
fatty
acids
is
clearly
evidenced
,
and
the
chimeric
dimers
provide
a
novel
tool
to
study
substrate
specificity
of
peroxisomal
ATP-binding
cassette
transporters
.
Diseases
Validation
Diseases presenting
"very long-chain fatty acids"
symptom
adrenomyeloneuropathy
neonatal adrenoleukodystrophy
x-linked adrenoleukodystrophy
zellweger syndrome
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