Science Signaling,
Год журнала:
2015,
Номер
8(408)
Опубликована: Дек. 22, 2015
The
Ca(2+)
release-activated
channel
mediates
influx
in
a
plethora
of
cell
types,
thereby
controlling
diverse
cellular
functions.
complex
is
composed
stromal
interaction
molecule
1
(STIM1),
an
endoplasmic
reticulum
Ca(2+)-sensing
protein,
and
Orai1,
plasma
membrane
channel.
Channels
STIM1
Orai1
mediate
even
at
low
extracellular
concentrations.
We
investigated
whether
the
activity
adapted
to
different
environmental
used
homology
modeling
molecular
dynamics
simulations
predict
presence
Ca(2+)-accumulating
region
(CAR)
pore
entrance
Orai1.
Furthermore,
proteins
with
mutations
CAR,
along
live-cell
experiments,
or
electrophysiological
recordings
transient,
electrostatic
loop3
interacting
loop1
(the
site
CAR)
determined
that
CAR
enhanced
permeation
most
efficiently
external
Consistent
these
results,
cells
expressing
mutants
exhibited
impaired
gene
expression
stimulated
by
Ca(2+)-activated
transcription
factor
nuclear
activated
T
(NFAT).
propose
architecture
close
proximity
selectivity
filter,
which
enables
Ca(2+)-selective
ion
permeation,
enhances
local
concentration
maintain
Ca(2+)-dependent
regulation
environments
relatively
Ca(2+)concentrations.
Reactive
oxygen
species
(ROS)
are
emerging
as
important
regulators
of
cancer
growth
and
metastatic
spread.
However,
how
cells
integrate
redox
signals
to
affect
progression
is
not
fully
understood.
Mitochondria
cellular
hubs,
which
highly
regulated
by
interactions
with
neighboring
organelles.
Here,
we
investigated
ROS
at
the
endoplasmic
reticulum
(ER)-mitochondria
interface
generated
translated
melanoma
outcome.
We
show
that
TMX1
TMX3
oxidoreductases,
promote
ER-mitochondria
communication,
upregulated
in
patient
samples.
TMX
knockdown
altered
mitochondrial
organization,
enhanced
bioenergetics,
elevated
mitochondrial-
NOX4-derived
ROS.
The
TMX-knockdown-induced
oxidative
stress
suppressed
proliferation,
migration,
xenograft
tumor
inhibiting
NFAT1.
Furthermore,
identified
NFAT1-positive
NFAT1-negative
subgroups,
wherein
NFAT1
expression
correlates
stage
potential.
Integrative
bioinformatics
revealed
genes
coding
for
redox-related
proteins
under
control
indicated
TMX1,
TMX3,
associated
poor
disease
Our
study
unravels
a
novel
redox-controlled
ER-mitochondria-NFAT1
signaling
loop
regulates
pathobiology
provides
biomarkers
indicative
aggressive
disease.
Proceedings of the National Academy of Sciences,
Год журнала:
2018,
Номер
115(15)
Опубликована: Март 26, 2018
Significance
The
work
presents
a
unique
understanding
of
the
organization
and
function
two
ubiquitously
expressed
proteins,
central
in
generating
calcium
signals
all
cell
types.
These
are
intracellular
sensing
“STIM”
highly
selective
surface
“Orai”
channels.
We
reveal
that
STIM
proteins
can
cross-link
Orai
channels,
resulting
reorganized
microenvironment
within
membrane
junctions
which
they
function,
with
important
consequences
generation
oscillatory
signals.
Interestingly,
we
show
variant
protein
widely
cells
functions
to
prevent
STIM–Orai
cross-linking
clustering
This
provides
modulation
signal
serve
protect
from
overstimulation
signaling
machinery.
Cardiovascular Research,
Год журнала:
2016,
Номер
110(3), С. 395 - 407
Опубликована: Апрель 18, 2016
3′,5′-Cyclic
adenosine
monophosphate
(cAMP)
signals
in
the
heart
are
often
confined
to
concentration
microdomains
shaped
by
cAMP
diffusion
and
enzymatic
degradation.
While
importance
of
phosphodiesterases
(degradative
enzymes)
sculpting
is
well
established
cardiomyocytes,
less
known
about
diffusivity
(DcAMP)
factors
affecting
it.
Many
earlier
studies
have
reported
fast
diffusivity,
which
argues
against
sharply
defined
microdomains.
[cAMP]
dynamics
cytoplasm
adult
rat
ventricular
myocytes
were
imaged
using
a
fourth
generation
genetically
encoded
FRET-based
sensor.
The
[cAMP]-response
addition
removal
isoproterenol
(β-adrenoceptor
agonist)
quantified
rates
synthesis
To
obtain
read
out
DcAMP,
stable
gradient
was
generated
microfluidic
device
delivered
agonist
one
half
myocyte
only.
After
accounting
for
phosphodiesterase
activity,
DcAMP
calculated
be
32
µm2/s;
an
order
magnitude
lower
than
water.
Diffusivity
independent
amount
produced.
Saturating
cAMP-binding
sites
with
analogue
6-Bnz-cAMP
did
not
accelerate
arguing
role
buffering
restricting
mobility.
diffused
at
comparable
rate
chemically
unrelated
but
similar
sized
molecules,
common
physical
cause
restricted
diffusivity.
Lower
mitochondrial
density
neonatal
cardiac
allowed
faster
diffusion,
demonstrating
mitochondria
as
barriers
In
myocytes,
tortuosity
due
barriers,
notably
mitochondria,
restricts
levels
that
more
compatible
microdomain
signalling.
Science Signaling,
Год журнала:
2015,
Номер
8(408)
Опубликована: Дек. 22, 2015
The
Ca(2+)
release-activated
channel
mediates
influx
in
a
plethora
of
cell
types,
thereby
controlling
diverse
cellular
functions.
complex
is
composed
stromal
interaction
molecule
1
(STIM1),
an
endoplasmic
reticulum
Ca(2+)-sensing
protein,
and
Orai1,
plasma
membrane
channel.
Channels
STIM1
Orai1
mediate
even
at
low
extracellular
concentrations.
We
investigated
whether
the
activity
adapted
to
different
environmental
used
homology
modeling
molecular
dynamics
simulations
predict
presence
Ca(2+)-accumulating
region
(CAR)
pore
entrance
Orai1.
Furthermore,
proteins
with
mutations
CAR,
along
live-cell
experiments,
or
electrophysiological
recordings
transient,
electrostatic
loop3
interacting
loop1
(the
site
CAR)
determined
that
CAR
enhanced
permeation
most
efficiently
external
Consistent
these
results,
cells
expressing
mutants
exhibited
impaired
gene
expression
stimulated
by
Ca(2+)-activated
transcription
factor
nuclear
activated
T
(NFAT).
propose
architecture
close
proximity
selectivity
filter,
which
enables
Ca(2+)-selective
ion
permeation,
enhances
local
concentration
maintain
Ca(2+)-dependent
regulation
environments
relatively
Ca(2+)concentrations.