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Structural basis of TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound form.
[holt-oram syndrome]
TBX
5
,
a
member
of
the
T
-
box
transcription
factor
family
,
plays
an
important
role
in
heart
and
limb
development
.
More
than
60
single
point
or
deletion
mutations
of
human
TBX
5
are
associated
with
Holt-
Oram
syndrome
that
manifests
itself
as
heart
and
limb
malformations
in
1
out
of
100
,
000
live
births
.
The
majority
of
these
mutations
are
located
in
the
TBX
5
T
-
box
domain
.
We
solved
the
crystal
structures
of
the
human
TBX
5
T
-
box
domain
in
its
DNA-unbound
form
and
in
complex
with
a
natural
DNA
target
site
allowing
for
the
first
time
the
comparison
between
unbound
and
DNA-bound
forms
.
Our
analysis
identifies
a
3
(
10
)
-
helix
at
the
C-
terminus
of
the
T
-
box
domain
as
an
inducible
recognition
element
,
critically
required
for
the
interaction
with
DNA
,
as
it
only
forms
upon
DNA
binding
and
is
unstructured
in
the
DNA-unbound
form
.
Using
circular
dichroism
,
we
characterized
the
thermal
stability
of
six
TBX
5
mutants
containing
single
point
mutations
in
the
T
-
box
domain
(
M
74
V
,
G
8
0
R
,
W
121
G
,
G
169
R
,
T
22
3
M
,
and
R
237
W
)
and
compared
them
with
wild-
type
protein
.
Mutants
G
8
0
R
and
W
121
G
show
drastically
reduced
thermal
stability
,
while
the
other
mutants
only
show
a
marginal
stability
decrease
.
For
all
TBX
5
mutants
,
binding
affinities
to
specific
and
nonspecific
DNA
sequences
were
determined
using
isothermal
titration
calorimetry
.
All
TBX
5
mutants
show
reduced
binding
affinities
to
a
specific
DNA
target
site
,
although
to
various
degrees
.
Interestingly
,
all
tested
TBX
5
mutants
differ
in
their
ability
to
bind
unspecific
DNA
,
indicating
that
both
sequence-
specific
and
unspecific
binding
might
contribute
to
the
misregulation
of
target
gene
expression
.
Diseases
Validation
Diseases presenting
"that both sequence-specific"
symptom
holt-oram syndrome
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