Rare Diseases Symptoms Automatic Extraction
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A random Abstract
Our Project
Our Team
Insights into Krabbe disease from structures of galactocerebrosidase.
[krabbe disease]
Krabbe
disease
is
a
devastating
neurodegenerative
disease
characterized
by
widespread
demyelination
that
is
caused
by
defects
in
the
enzyme
galactocerebrosidase
(
GALC
)
.
Disease-causing
mutations
have
been
identified
throughout
the
GALC
gene
.
However
,
a
molecular
understanding
of
the
effect
of
these
mutations
has
been
hampered
by
the
lack
of
structural
data
for
this
enzyme
.
Here
we
present
the
crystal
structures
of
GALC
and
the
GALC
-product
complex
,
revealing
a
novel
domain
architecture
with
a
previously
uncharacterized
lectin
domain
not
observed
in
other
hydrolases
.
All
three
domains
of
GALC
contribute
residues
to
the
substrate-binding
pocket
,
and
disease-causing
mutations
are
widely
distributed
throughout
the
protein
.
Our
structures
provide
an
essential
insight
into
the
diverse
effects
of
pathogenic
mutations
on
GALC
function
in
human
Krabbe
variants
and
a
compelling
explanation
for
the
severity
of
many
mutations
associated
with
fatal
infantile
disease
.
The
localization
of
disease-associated
mutations
in
the
structure
of
GALC
will
facilitate
identification
of
those
patients
that
would
be
responsive
to
pharmacological
chaperone
therapies
.
Furthermore
,
our
structure
provides
the
atomic
framework
for
the
design
of
such
drugs
.