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Catalytic activities of Werner protein are affected by adduction with 4-hydroxy-2-nonenal.
[werner syndrome]
4
-
Hydroxy-
2
-
nonenal
(
HNE
)
is
a
reactive
α
,
β-unsaturated
aldehyde
generated
during
oxidative
stress
and
subsequent
peroxidation
of
polyunsaturated
fatty
acids
.
Here
,
Werner
protein
(
WRN
)
was
identified
as
a
novel
target
for
modification
by
HNE
.
Werner
syndrome
arises
through
mutations
in
the
WRN
gene
that
encodes
the
RecQ
DNA
helicase
which
is
critical
for
maintaining
genomic
stability
.
This
hereditary
disease
is
associated
with
chromosomal
instability
,
premature
aging
and
cancer
predisposition
.
WRN
appears
to
participate
in
the
cellular
response
to
oxidative
stress
and
cells
devoid
of
WRN
display
elevated
levels
of
oxidative
DNA
damage
.
We
demonstrated
that
helicase
/
ATPase
and
exonuclease
activities
of
HNE-modified
WRN
protein
were
inhibited
both
in
vitro
and
in
immunocomplexes
purified
from
the
cell
extracts
.
Sites
of
HNE
adduction
in
human
WRN
were
identified
at
Lys
577
,
Cys
727
,
His
1290
,
Cys
1367
,
Lys
1371
and
Lys
1389
.
We
applied
in
silico
modeling
of
the
helicase
and
RQC
domains
of
WRN
protein
with
HNE
adducted
to
Lys
577
and
Cys
727
and
provided
a
potential
mechanism
of
the
observed
deregulation
of
the
protein
catalytic
activities
.
In
light
of
the
obtained
results
,
we
postulate
that
HNE
adduction
to
WRN
is
a
post-translational
modification
,
which
may
affect
WRN
conformational
stability
and
function
,
contributing
to
features
and
diseases
associated
with
premature
senescence
.
Diseases
Validation
Diseases presenting
"elevated levels"
symptom
22q11.2 deletion syndrome
adrenal incidentaloma
adrenomyeloneuropathy
alexander disease
aniridia
cadasil
canavan disease
congenital adrenal hyperplasia
epidermolysis bullosa simplex
erythropoietic protoporphyria
esophageal carcinoma
fabry disease
familial hypocalciuric hypercalcemia
hereditary cerebral hemorrhage with amyloidosis
inclusion body myositis
kabuki syndrome
omenn syndrome
phenylketonuria
primary effusion lymphoma
pyruvate dehydrogenase deficiency
scrub typhus
sneddon syndrome
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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