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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
"skin fibroblasts"
symptom
child syndrome
cowden syndrome
cystinuria
dentinogenesis imperfecta
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
gm1 gangliosidosis
homocystinuria without methylmalonic aciduria
krabbe disease
malignant atrophic papulosis
monosomy 21
neonatal adrenoleukodystrophy
pyruvate dehydrogenase deficiency
werner syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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