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Carrier subunit of plasma membrane transporter is required for oxidative folding of its helper subunit.
[cystinuria]
We
study
the
amino
acid
transport
system
b
(
0
,
+
)
as
a
model
for
folding
,
assembly
,
and
early
traffic
of
membrane
protein
complexes
.
System
b
(
0
,
+
)
is
made
of
two
disulfide-linked
membrane
subunits
:
the
carrier
,
b
(
0
,
+
)
amino
acid
transporter
(
b
(
0
,
+
)
AT
)
,
a
polytopic
protein
,
and
the
helper
,
related
to
b
(
0
,
+
)
amino
acid
transporter
(
rBAT
)
,
a
type
II
glycoprotein
.
rBAT
ectodomain
mutants
display
folding
/
trafficking
defects
that
lead
to
type
I
cystinuria
.
Here
we
show
that
,
in
the
presence
of
b
(
0
,
+
)
AT
,
three
disulfides
were
formed
in
the
rBAT
ectodomain
.
Disulfides
Cys-
242
-
Cys-
273
and
Cys-
571
-
Cys-
666
were
essential
for
biogenesis
.
Cys-
673
-
Cys-
685
was
dispensable
,
but
the
single
mutants
C
6
73
S
,
and
C
6
85
S
showed
compromised
stability
and
trafficking
.
Cys-
242
-
Cys-
273
likely
was
the
first
disulfide
to
form
,
and
unpaired
Cys-
242
or
Cys-
273
disrupted
oxidative
folding
.
Strikingly
,
unassembled
rBAT
was
found
as
an
ensemble
of
different
redox
species
,
mainly
monomeric
.
The
ensemble
did
not
change
upon
inhibition
of
rBAT
degradation
.
Overall
,
these
results
indicated
a
b
(
0
,
+
)
AT-dependent
oxidative
folding
of
the
rBAT
ectodomain
,
with
the
initial
and
probably
cotranslational
formation
of
Cys-
242
-
Cys-
273
,
followed
by
the
oxidation
of
Cys-
571
-
Cys-
666
and
Cys-
673
-
Cys-
685
,
that
was
completed
posttranslationally
.
Diseases
Validation
Diseases presenting
"a b"
symptom
cystinuria
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