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The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2.
[omenn syndrome]
Recombination
activating
gene
(
RAG
)
1
and
RAG
2
together
catalyze
V
(
D
)
J
gene
rearrangement
in
lymphocytes
as
the
first
step
in
the
assembly
and
maturation
of
antigen
receptors
.
RAG
2
contains
a
plant
homeodomain
(
PHD
)
near
its
C
terminus
(
RAG
2
-
PHD
)
that
recognizes
histone
H
3
methylated
at
lysine
4
(
H
3
K
4
me
)
and
influences
V
(
D
)
J
recombination
.
We
report
here
crystal
structures
of
RAG
2
-
PHD
alone
and
complexed
with
five
modified
H
3
peptides
.
Two
aspects
of
RAG
2
-
PHD
are
unique
.
First
,
in
the
absence
of
the
modified
peptide
,
a
peptide
N-
terminal
to
RAG
2
-
PHD
occupies
the
substrate-binding
site
,
which
may
reflect
an
autoregulatory
mechanism
.
Second
,
in
contrast
to
other
H
3
K
4
me
3
-
binding
PHD
domains
,
RAG
2
-
PHD
substitutes
a
carboxylate
that
interacts
with
arginine
2
(
R
2
)
with
a
Tyr
,
resulting
in
binding
to
H
3
K
4
me
3
that
is
enhanced
rather
than
inhibited
by
dimethylation
of
R
2
.
Five
residues
involved
in
histone
H
3
recognition
were
found
mutated
in
severe
combined
immunodeficiency
(
SCID
)
patients
.
Disruption
of
the
RAG
2
-
PHD
structure
appears
to
lead
to
the
absence
of
T
and
B
lymphocytes
,
whereas
failure
to
bind
H
3
K
4
me
3
is
linked
to
Omenn
Syndrome
.
This
work
provides
a
molecular
basis
for
chromatin-dependent
gene
recombination
and
presents
a
single
protein
domain
that
simultaneously
recognizes
two
distinct
histone
modifications
,
revealing
added
complexity
in
the
read-out
of
combinatorial
histone
modifications
.
Diseases
Validation
Diseases presenting
"absence of t"
symptom
omenn syndrome
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