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Structure of aspartoacylase, the brain enzyme impaired in Canavan disease.
[canavan disease]
Aspartoacylase
catalyzes
hydrolysis
of
N-
acetyl-l-aspartate
to
aspartate
and
acetate
in
the
vertebrate
brain
.
Deficiency
in
this
activity
leads
to
spongiform
degeneration
of
the
white
matter
of
the
brain
and
is
the
established
cause
of
Canavan
disease
,
a
fatal
progressive
leukodystrophy
affecting
young
children
.
We
present
crystal
structures
of
recombinant
human
and
rat
aspartoacylase
refined
to
2
.
8
-
and
1
.
8
-
A
resolution
,
respectively
.
The
structures
revealed
that
the
N-
terminal
domain
of
aspartoacylase
adopts
a
protein
fold
similar
to
that
of
zinc-dependent
hydrolases
related
to
carboxypeptidases
A
.
The
catalytic
site
of
aspartoacylase
shows
close
structural
similarity
to
those
of
carboxypeptidases
despite
only
10
-
13
%
sequence
identity
between
these
proteins
.
About
100
C-
terminal
residues
of
aspartoacylase
form
a
globular
domain
with
a
two
-stranded
beta
-sheet
linker
that
wraps
around
the
N-
terminal
domain
.
The
long
channel
leading
to
the
active
site
is
formed
by
the
interface
of
the
N-
and
C-
terminal
domains
.
The
C-
terminal
domain
is
positioned
in
a
way
that
prevents
productive
binding
of
polypeptides
in
the
active
site
.
The
structures
revealed
that
residues
158
-
164
may
undergo
a
conformational
change
that
results
in
opening
and
partial
closing
of
the
channel
entrance
.
We
hypothesize
that
the
catalytic
mechanism
of
aspartoacylase
is
closely
analogous
to
that
of
carboxypeptidases
.
We
identify
residues
involved
in
zinc
coordination
,
and
propose
which
residues
may
be
involved
in
substrate
binding
and
catalysis
.
The
structures
also
provide
a
structural
framework
necessary
for
understanding
the
deleterious
effects
of
many
missense
mutations
of
human
aspartoacylase
.