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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
"type protein"
symptom
classical phenylketonuria
hereditary cerebral hemorrhage with amyloidosis
holt-oram syndrome
homocystinuria without methylmalonic aciduria
kallmann syndrome
neonatal adrenoleukodystrophy
oculocutaneous albinism
omenn syndrome
waldenström macroglobulinemia
x-linked adrenoleukodystrophy
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