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DNA binding residues in the RQC domain of Werner protein are critical for its catalytic activities.
[werner syndrome]
Werner
protein
(
WRN
)
,
member
of
the
RecQ
helicase
family
,
is
a
helicase
and
exonuclease
,
and
participates
in
multiple
DNA
metabolic
processes
including
DNA
replication
,
recombination
and
DNA
repair
.
Mutations
in
the
WRN
gene
cause
Werner
syndrome
,
associated
with
premature
aging
,
genome
instability
and
cancer
predisposition
.
The
RecQ
C-
terminal
(
RQC
)
domain
of
WRN
,
containing
α
2
-
α
3
loop
and
β-wing
motifs
,
is
important
for
DNA
binding
and
for
many
protein
interactions
.
To
better
understand
the
critical
functions
of
this
domain
,
we
generated
recombinant
WRN
proteins
(
using
a
novel
purification
scheme
)
with
mutations
in
Arg-
993
within
the
α
2
-
α
3
loop
of
the
RQC
domain
and
in
Phe-
1037
of
the
-
wing
motif
.
We
then
studied
the
catalytic
activities
and
DNA
binding
of
these
mutant
proteins
as
well
as
some
important
functional
protein
interactions
.
The
mutant
proteins
were
defective
in
DNA
binding
and
helicase
activity
,
and
interestingly
,
they
had
deficient
exonuclease
activity
and
strand
annealing
function
.
The
RQC
domain
of
WRN
has
not
previously
been
implicated
in
exonuclease
or
annealing
activities
.
The
mutant
proteins
could
not
stimulate
NEIL
1
incision
activity
as
did
the
wild
type
.
Thus
,
the
Arg-
993
and
Phe-
1037
in
the
RQC
domain
play
essential
roles
in
catalytic
activity
,
and
in
functional
interactions
mediated
by
WRN
.
Diseases
Validation
Diseases presenting
"premature aging"
symptom
alexander disease
cadasil
cushing syndrome
kindler syndrome
werner syndrome
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