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Quantitative analysis of peroxisomal targeting signal type-1 binding to wild-type and pathogenic mutants of Pex5p supports an affinity threshold for peroxisomal protein targeting.
[zellweger syndrome]
Peroxisomal
biogenesis
disorders
(
PBDs
)
are
caused
by
mutations
in
12
distinct
genes
that
encode
the
components
of
the
peroxisome
assembly
machinery
.
Three
mutations
in
the
gene
encoding
Pex
5
p
,
the
peroxisomal
targeting
signal
type
-
1
(
PTS
1
)
receptor
,
have
been
reported
,
each
associated
with
a
disorder
of
the
Zellweger
spectrum
of
different
severity
.
Here
,
we
report
studies
of
the
affinities
of
mutated
forms
of
Pex
5
p
for
a
series
of
PTS
1
peptides
and
conclude
that
PTS
1
-
affinity
reductions
are
correlated
with
disease
severity
and
cell
biological
phenotype
.
A
quantitative
model
has
been
developed
that
allows
estimation
of
the
dissociation
constants
for
complexes
with
a
wide
range
of
PTS
1
sequences
bound
to
wild-
type
and
mutant
Pex
5
p
.
In
the
context
of
this
model
,
the
binding
measurements
suggest
that
no
PTS
1
-
containing
proteins
are
targeted
by
Pex
5
p
(
N
489
K
)
and
only
a
relatively
small
subset
of
PTS
1
-
containing
proteins
with
the
highest
affinity
for
Pex
5
p
are
targeted
to
peroxisomes
by
Pex
5
p
(
S
563
W
)
.
Furthermore
,
the
results
of
the
analysis
are
consistent
with
an
approximate
dissociation
constant
threshold
near
500
nM
required
for
efficient
protein
targeting
to
peroxisomes
.
Diseases
Validation
Diseases presenting
"a disorder of the zellweger spectrum of different severity"
symptom
zellweger syndrome
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