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Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum patient reveals novel homooligomerization of PEX13 and its role in human peroxisome biogenesis.
[zellweger syndrome]
In
humans
,
the
concerted
action
of
at
least
13
different
peroxisomal
PEX
proteins
is
needed
for
proper
peroxisome
biogenesis
.
Mutations
in
any
of
these
PEX
genes
can
lead
to
lethal
neurometabolic
disorders
of
the
Zellweger
syndrome
spectrum
(
ZSS
)
.
Previously
,
we
identified
the
W
313
G
mutation
located
within
the
SH
3
domain
of
the
peroxisomal
protein
,
PEX
13
.
As
this
tryptophan
residue
is
highly
conserved
in
almost
all
known
SH
3
proteins
,
we
investigated
the
pathogenic
mechanism
of
the
W
313
G
mutation
and
its
role
in
PEX
13
interactions
and
functions
in
peroxisome
biogenesis
.
Here
,
we
report
for
the
first
time
that
human
PEX
13
interacts
with
itself
in
peroxisomes
in
living
cells
.
We
demonstrate
that
the
import
of
PTS
1
(
peroxisomal
targeting
signal
1
)
proteins
is
specifically
disrupted
when
homooligomerization
of
PEX
13
is
interrupted
.
Live
cell
FRET
microscopy
in
living
cells
as
well
as
co
-immunoprecipitation
experiments
reveal
that
the
highly
conserved
W
313
residue
is
important
for
self-association
of
PEX
13
but
is
not
required
for
interaction
with
PEX
14
,
a
well-established
interaction
partner
at
the
peroxisomal
membrane
.
Experiments
with
truncated
constructs
indicate
that
although
the
W
313
G
mutation
resides
in
the
C-
terminal
SH
3
domain
,
the
N-
terminal
half
is
necessary
for
peroxisomal
localization
,
which
in
turn
appears
to
be
crucial
for
homooligomerization
.
Furthermore
,
rescue
of
homooligomerization
in
the
W
313
G
mutant
cells
through
complementation
with
truncation
constructs
restores
import
of
peroxisomal
matrix
proteins
.
Taken
together
,
the
thorough
analyses
of
a
ZSS
patient
mutation
unraveled
the
general
cell
biological
function
of
PEX
13
and
its
mechanism
in
the
import
of
peroxisomal
matrix
PTS
1
proteins
.
Diseases
Validation
Diseases presenting
"lethal neurometabolic disorders"
symptom
zellweger syndrome
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