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Involvement of the carboxyl-terminal region of the yeast peroxisomal half ABC transporter Pxa2p in its interaction with Pxa1p and in transporter function.
[x-linked adrenoleukodystrophy]
The
peroxisome
is
a
single
membrane-bound
organelle
in
eukaryotic
cells
involved
in
lipid
metabolism
,
including
β-oxidation
of
fatty
acids
.
The
human
genetic
disorder
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
is
caused
by
mutations
in
the
ABCD
1
gene
(
encoding
ALDP
,
a
peroxisomal
half
ATP-binding
cassette
[
ABC
]
transporter
)
.
This
disease
is
characterized
by
defective
peroxisomal
β-oxidation
and
a
large
accumulation
of
very
long
-chain
fatty
acids
in
brain
white
matter
,
adrenal
cortex
,
and
testis
.
ALDP
forms
a
homodimer
proposed
to
be
the
functional
transporter
,
whereas
the
peroxisomal
transporter
in
yeast
is
a
heterodimer
comprising
two
half
ABC
transporters
,
Pxa
1
p
and
Pxa
2
p
,
both
orthologs
of
human
ALDP
.
While
the
carboxyl-terminal
domain
of
ALDP
is
engaged
in
dimerization
,
it
remains
unknown
whether
the
same
region
is
involved
in
the
interaction
between
Pxa
1
p
and
Pxa
2
p
.
U
sing
a
yeast
two
-hybrid
assay
,
we
found
that
the
carboxyl-terminal
region
(
CT
)
of
Pxa
2
p
,
but
not
of
Pxa
1
p
,
is
required
for
their
interaction
.
Further
analysis
indicated
that
the
central
part
of
the
CT
(
designated
CT
2
)
of
Pxa
2
p
was
indispensable
for
its
interaction
with
the
carboxyl
terminally
truncated
Pxa
1
_
NBD
.
An
interaction
between
the
CT
of
Pxa
2
p
and
Pxa
1
_
NBD
was
not
detected
,
but
could
be
identified
in
the
presence
of
Pxa
2
_
NBD-
CT
1
.
A
single
mutation
of
two
conserved
residues
(
aligned
with
X-
ALD
-associated
mutations
at
the
same
positions
in
ALDP
)
in
the
CT
2
of
the
Pxa
2
_
NBD-
CT
protein
impaired
its
interaction
with
Pxa
1
_
NBD
or
Pxa
1
_
NBD-
CT
,
resulting
in
a
mutant
protein
that
exhibited
a
proteinase
K
digestion
profile
different
from
that
of
the
wild-
type
protein
.
Functional
analysis
of
these
mutant
proteins
on
oleate
plates
indicated
that
they
were
defective
in
transporter
function
.
The
CT
of
Pxa
2
p
is
involved
in
its
interaction
with
Pxa
1
p
and
in
transporter
function
.
This
concept
may
be
applied
to
human
ALDP
studies
,
helping
to
establish
the
pathological
mechanism
for
CT
-related
X-
ALD
disease
.
Diseases
Validation
Diseases presenting
"white matter"
symptom
22q11.2 deletion syndrome
adrenomyeloneuropathy
alexander disease
cadasil
canavan disease
classical phenylketonuria
cushing syndrome
gm1 gangliosidosis
hereditary cerebral hemorrhage with amyloidosis
homocystinuria without methylmalonic aciduria
kabuki syndrome
kallmann syndrome
krabbe disease
neonatal adrenoleukodystrophy
proteus syndrome
pyruvate dehydrogenase deficiency
sneddon syndrome
wiskott-aldrich syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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