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A random Abstract
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Structure of GroEL in complex with an early folding intermediate of alanine glyoxylate aminotransferase.
[primary hyperoxaluria type 1]
Primary
hyperoxaluria
type
1
is
a
rare
autosomal
recessive
disease
caused
by
mutations
in
the
alanine
glyoxylate
aminotransferase
gene
(
AGXT
)
.
We
have
previously
shown
that
P
11
L
and
I
340
M
polymorphisms
together
with
I
244
T
mutation
(
AGXT
-LTM
)
represent
a
conformational
disease
that
could
be
amenable
to
pharmacological
intervention
.
Thus
,
the
study
of
the
folding
mechanism
of
AGXT
is
crucial
to
understand
the
molecular
basis
of
the
disease
.
Here
,
we
provide
biochemical
and
structural
data
showing
that
AGXT
-LTM
is
able
to
form
non-native
folding
intermediates
.
The
three
-dimensional
structure
of
a
complex
between
the
bacterial
chaperonin
GroEL
and
a
folding
intermediate
of
AGXT
-LTM
mutant
has
been
solved
by
cryoelectron
microscopy
.
The
electron
density
map
shows
the
protein
substrate
in
a
non-native
extended
conformation
that
crosses
the
GroEL
central
cavity
.
Addition
of
ATP
to
the
complex
induces
conformational
changes
on
the
chaperonin
and
the
internalization
of
the
protein
substrate
into
the
folding
cavity
.
The
structure
provides
a
three
-dimensional
picture
of
an
in
vivo
early
ATP-dependent
step
of
the
folding
reaction
cycle
of
the
chaperonin
and
supports
a
GroEL
functional
model
in
which
the
chaperonin
promotes
folding
of
the
AGXT
-LTM
mutant
protein
through
forced
unfolding
mechanism
.