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Efficient trafficking of acidic proteins out of the endoplasmic reticulum involves a conserved amino terminal IleProVal (IPV)-like tripeptide motif.
[dentinogenesis imperfecta]
Most
of
the
proposed
extracellular
biomineralization
processes
include
the
secretion
of
proteins
that
interact
with
mineral
ions
and
/
or
mineral
surfaces
.
Typically
these
proteins
are
acidic
or
have
acidic
domains
that
interact
with
multivalent
cations
in
the
extracellular
environment
.
We
propose
that
most
acidic
,
Ca
(
2
+
)
-
binding
proteins
challenge
the
cell
's
mechanisms
for
trafficking
through
the
endoplasmic
reticulum
(
ER
)
lumen
due
to
lumenal
mM
calcium
that
cause
them
to
form
large
aggregates
.
We
have
recently
shown
that
>
95
%
of
the
DSPP
mutations
that
cause
non-syndromic
genetic
dentin
diseases
start
their
dominant
negative
affects
by
failing
to
rapidly
exit
the
ER
likely
by
forming
complexes
that
can
not
be
normally
trafficked
to
the
Golgi
.
The
complexes
of
mutant
DSPP
then
capture
more
(
severe
disease
)
or
less
(
mild
disease
)
of
the
DSPP
translated
from
the
normal
allele
.
After
searching
genomic
databases
as
well
as
the
published
literature
,
we
found
the
IleProVal
(
IPV
)
-
like
motif
at
the
predicted
amino
terminus
of
many
acidic
proteins
made
in
the
mineralizing
as
well
as
non-mineralizing
tissues
of
many
species
including
vertebrates
,
echinoderms
,
mollusks
,
and
yeast
.
While
we
often
focused
on
acidic
proteins
reported
associated
with
mineralizing
structures
,
proteins
associated
with
hormones
and
their
storage
/
secretion
,
digestion
,
blood
functions
,
as
well
as
milk
and
other
secreted
fluids
started
with
variations
of
the
motif
.
Our
hypothesis
is
that
the
IPV-like
motif
interacts
with
a
highly
conserved
cargo
receptor
in
the
ER
that
efficiently
traffics
the
acidic
proteins
out
of
the
organelle
before
they
can
form
harmful
aggregates
in
the
Ca
(
2
+
)
-
rich
lumen
.
Diseases
Validation
Diseases presenting
"many acidic proteins"
symptom
dentin dysplasia
dentinogenesis imperfecta
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