Proteins
occurring
in
significantly
high
concentrations
cellular
environments
(over
100
mg/mL)
and
functioning
crowded
cytoplasm,
often
face
the
prodigious
challenges
of
aggregation
which
are
pathological
hallmark
aging
critically
responsible
for
a
wide
spectrum
rising
human
diseases.
Here
we
combine
joint-venture
complementary
wet-lab
experiment
molecular
simulation
to
discern
potential
ability
adenosine
triphosphate
(ATP)
as
sollubilizer
protein
aggregates.
We
show
that
ATP
prevents
both
condensation
aggregation-prone
intrinsically
disordered
Aβ40
promotes
dissolution
pre-formed
Computer
links
ATP's
sollubilizing
role
its
modulate
protein's
structural
plasticity
by
unwinding
conformation.
is
positioned
superior
biological
solubilizer
aggregates
over
traditional
chemical
hydrotropes,
potentially
holding
promises
therapeutic
interventions
protein-aggregation
related
Going
beyond
conventional
activity
energy
currency,
amphiphilic
nature
enables
protein-specific
interaction
would
enhance
efficiency
processes.
Chemical Society Reviews,
Год журнала:
2024,
Номер
53(10), С. 4976 - 5013
Опубликована: Янв. 1, 2024
Protein
misfolding
and
amyloid
aggregation,
linked
to
neurodegenerative
diseases,
can
result
from
liquid–liquid
phase
separation
(LLPS)
a
subsequent
liquid-to-solid
transition.
This
represents
LLPS
as
generic
mechanism
in
nucleation.
Journal of the American Chemical Society,
Год журнала:
2024,
Номер
146(9), С. 6045 - 6052
Опубликована: Фев. 23, 2024
Many
cellular
coassemblies
of
proteins
and
polynucleotides
facilitate
liquid–liquid
phase
separation
(LLPS)
the
subsequent
self-assembly
disease-associated
amyloid
fibrils
within
liquid
droplets.
Here,
we
explore
dynamics
coupled
conformational
transitions
model
adenosine
triphosphate
(ATP)-binding
peptides,
ACC1–13Kn,
consisting
potent
amyloidogenic
fragment
insulin's
A-chain
(ACC1–13)
merged
with
oligolysine
segments
various
lengths
(Kn,
n
=
16,
24,
40).
The
ATP-stabilized
is
preceded
by
LLPS
for
peptides
sufficiently
long
segments.
two-component
droplets
are
in
dynamic
equilibria
free
ATP
monomeric
which
makes
them
susceptible
to
ATP-hydrolyzing
apyrase
ACC1–13Kn-digesting
proteinase
K.
Both
enzymes
capable
rapid
disassembly
fibrils,
producing
either
monomers
peptide
(apyrase)
or
released
together
cleaved-off
(proteinase
K).
In
latter
case,
enzyme-sequestered
Kn
form
co-released
ATP,
resulting
an
unusual
fibril-to-droplet
transition.
support
highly
nature
aggregate-monomer
equilibria,
addition
superstoichiometric
amounts
ACC1–13Kn-ATP
coaggregate
causes
its
disassembly.
Our
results
show
that
droplet
state
not
merely
intermediate
on
pathway
aggregate
but
may
also
constitute
final
a
complex
protein
misfolding
scenario
rich
degraded
fragments
incompetent
transition
again
into
fibrils.
Communications Chemistry,
Год журнала:
2024,
Номер
7(1)
Опубликована: Сен. 16, 2024
P53
Phase
separation
is
crucial
towards
amyloid
aggregation
and
p63
p73
have
enhanced
expression
in
tumors.
This
study
examines
the
phase
behaviors
of
p53,
p63,
p73.
Here
we
show
that
unlike
DNA-binding
domain
p53
(p53C),
p63C
p73C
undergo
separation,
but
do
not
form
amyloids
under
physiological
temperatures.
Wild-type
mutant
p53C
droplets
at
4°C
aggregates
37
°C
with
properties.
Mutant
promotes
amyloid-like
states
p73C,
recruiting
them
into
membraneless
organelles.
Amyloid
conversion
supported
by
thioflavin
T
Congo
red
binding,
increased
light
scattering,
circular
dichroism.
Full-length
(or
p73C)
co-transfection
shows
reduced
fluorescence
recovery
after
photobleaching.
Heparin
inhibits
prion-like
induced
p53C.
These
findings
highlight
role
initiating
p73,
opening
avenues
for
targeting
cancer
therapy.
The Journal of Physical Chemistry B,
Год журнала:
2023,
Номер
127(28), С. 6241 - 6250
Опубликована: Июль 6, 2023
Amyloid
aggregation
describes
the
aberrant
self-assembly
of
peptides
into
ordered
fibrils
characterized
by
cross-β
spine
cores
and
is
associated
with
many
neurodegenerative
diseases
Type
2
diabetes.
Oligomers,
populated
during
early
stage
aggregation,
are
found
to
be
more
cytotoxic
than
mature
fibrils.
Recently,
amyloidogenic
have
been
reported
undergo
liquid–liquid
phase
separation
(LLPS)─a
biological
process
important
for
compartmentalization
biomolecules
in
living
cells─prior
fibril
formation.
Understanding
relationship
between
LLPS
amyloid
especially
formation
oligomers,
essential
uncovering
disease
mechanisms
mitigating
toxicity.
In
this
Perspective,
available
theories
models
first
briefly
reviewed.
By
drawing
analogies
gas,
liquid,
solid
phases
thermodynamics,
a
diagram
protein
monomer,
droplet,
states
separated
coexistence
lines
can
inferred.
Due
high
free
energy
barrier
fibrillization
kinetically
delaying
seeds
out
droplets,
"hidden"
monomer-droplet
line
extends
phase.
then
described
as
equilibration
from
initial
"out-of-equilibrium"
state
homogeneous
solution
monomers
final
equilibrium
stable
coexisting
and/or
droplets
via
metastable
or
intermediates.
The
oligomers
also
discussed.
We
suggest
that
droplet
should
considered
future
studies
which
may
help
better
understand
develop
therapeutic
strategies
mitigate
Biological Chemistry,
Год журнала:
2023,
Номер
404(10), С. 897 - 908
Опубликована: Сен. 1, 2023
ATP
is
an
important
small
molecule
that
appears
at
outstandingly
high
concentration
within
the
cellular
medium.
Apart
from
its
use
as
a
source
of
energy
and
metabolite,
there
increasing
evidence
for
functions
cosolute
biomolecular
processes.
Owned
to
solubilizing
kosmotropic
triphosphate
hydrophobic
adenine
moieties,
versatile
can
interact
with
biomolecules
in
various
ways.
We
here
three
models
categorize
these
interactions
apply
them
review
recent
studies.
focus
on
impact
solubility,
folding
stability
phase
transitions.
This
leads
us
possible
implications
therapeutic
interventions
neurodegenerative
diseases.
ACS Chemical Neuroscience,
Год журнала:
2023,
Номер
14(19), С. 3655 - 3664
Опубликована: Сен. 18, 2023
Amyloid-β
[Aβ(1-40)]
aggregation
into
a
fibrillar
network
is
one
of
the
major
hallmarks
Alzheimer's
disease
(AD).
Recently,
few
studies
reported
that
polyphosphate
(polyP),
an
anionic
biopolymer
participates
in
various
cellular
physiological
processes
humans,
induces
fibrilization
many
amyloidogenic
proteins
[
2020
Disease
Facts
and
Figures;
John
Wiley
Sons
Inc.,
2020;
Tanzi,
R.
E.;
Bertram,
L.
Cell
2005,
120,
545-555;
Selkoe,
D.
J.
Proc.
Natl.
Acad.
Sci.
U.S.A.
1995,
275,
630-631;
Rambaran,
N.;
Serpell,
C.
Prion
2008,
2,
112-117].
However,
role
polyP
Aβ(1-40)
underlying
mechanism
are
unclear.
In
this
study,
we
report
experimental
investigations
on
kinetics
Aβ(1-40).
It
found
exhibits
dual
effect
depending
upon
pH
value.
At
=
7
(neutral),
inhibits
amyloid
dose-dependent
manner
similar
to
negatively
charged
nanoparticles.
On
contrary,
at
3
(acidic),
accelerates
via
liquid-liquid
phase
separation
(LLPS),
wherein
protein-rich
droplets
contain
mature
fibrils.
parameter
space
spanned
by
concentrations
polyP,
diagram
constructed
demark
domain
where
LLPS
observed
3.
Characterization
protein
aggregates,
secondary
structure
content
cell
viability
presence
aggregates
discussed
both
values.
This
study
reveals
biopolymers
can
modulate
kinetics,
linked
neurodegenerative
diseases,
their
local
pH.
Liquid-to-solid-like
phase
transition
(LSPT)
of
disordered
proteins
via
metastable
liquid-like
droplets
is
a
well-documented
phenomenon
in
biology
and
linked
to
many
pathological
conditions
including
neurodegenerative
diseases.
However,
very
less
known
about
the
early
microscopic
events
transient
intermediates
involved
irreversible
protein
aggregation
functional
globular
proteins.
Herein,
using
range
spectroscopic
techniques,
we
show
that
LSPT
protein,
human
serum
albumin
(HSA),
exclusively
driven
by
spontaneous
coalescence
involving
various
temporal
manner.
We
interdroplet
communication
essential
for
both
initial
growth
amorphous
aggregates
within
individual
droplets,
which
subsequently
transform
amyloid-like
fibrils.
Immobilized
neither
any
nucleation
nor
upon
aging.
Moreover,
found
exchange
materials
with
dilute
dispersed
has
negligible
influence
on
HSA.
Our
findings
reveal
interfacial
properties
effectively
modulate
feasibility
kinetics
HSA
ligand
binding,
suggesting
possible
regulatory
mechanism
cells
utilize
control
dynamics
LSPT.
Furthermore,
dynamic
heterogeneous
droplet
assembly
two
proteins,
transferrin
(Tf),
an
intriguing
fused
where
solid-like
phases
coexist
same
droplet,
eventually
mixed
fibrillar
assembly.
These
insights
not
only
highlight
importance
interactions
behind
biomolecules
but
also
showcase
its
adverse
effect
structure
function
other
crowded
Scientific Reports,
Год журнала:
2024,
Номер
14(1)
Опубликована: Апрель 17, 2024
Abstract
Intracellular
aggregation
of
fused
in
sarcoma
(FUS)
is
associated
with
the
pathogenesis
familial
amyotrophic
lateral
sclerosis
(ALS).
Under
stress,
FUS
forms
liquid
droplets
via
liquid–liquid
phase
separation
(LLPS).
Two
types
wild-type
LLPS
exist
equilibrium:
low-pressure
(LP-LLPS)
and
high-pressure
(HP-LLPS);
former
dominates
below
2
kbar
latter
over
kbar.
Although
several
disease-type
variants
have
been
identified,
molecular
mechanism
underlying
accelerated
cytoplasmic
granule
formation
ALS
patients
remains
poorly
understood.
Herein,
we
report
reversible
two
states
irreversible
liquid–solid
transition,
namely
droplet
aging,
patient-type
variant
R495X
using
fluorescence
microscopy
ultraviolet–visible
absorption
spectroscopy
combined
perturbations
pressure
temperature.
Liquid-to-solid
transition
was
HP-LLPS
than
variant;
arginine
slowed
aging
at
atmospheric
conditions
by
inhibiting
more
selectively
compared
to
that
LP-LLPS.
Our
findings
provide
new
insight
into
which
readily
aggregates.
Targeting
aberrantly
formed
(the
state)
proteins
minimal
impact
on
physiological
functions
could
be
a
novel
therapeutic
strategy
for
LLPS-mediated
protein
diseases.
Proteins
occurring
in
significantly
high
concentrations
cellular
environments
(over
100
mg/ml)
and
functioning
crowded
cytoplasm,
often
face
the
prodigious
challenges
of
aggregation
which
are
pathological
hallmark
aging
critically
responsible
for
a
wide
spectrum
rising
human
diseases.
Here,
we
combine
joint-venture
complementary
wet-lab
experiment
molecular
simulation
to
discern
potential
ability
adenosine
triphosphate
(ATP)
as
solubilizer
protein
aggregates.
We
show
that
ATP
prevents
both
condensation
aggregation-prone
intrinsically
disordered
Aβ40
promotes
dissolution
preformed
Computer
links
ATP’s
solubilizing
role
its
modulate
protein’s
structural
plasticity
by
unwinding
conformation.
is
positioned
superior
biological
aggregates
over
traditional
chemical
hydrotropes,
potentially
holding
promises
therapeutic
interventions
protein-aggregation-related
Going
beyond
conventional
activity
energy
currency,
amphiphilic
nature
enables
protein-specific
interaction
would
enhance
efficiency
processes.
Proteins
occurring
in
significantly
high
concentrations
cellular
environments
(over
100
mg/mL)
and
functioning
crowded
cytoplasm,
often
face
the
prodigious
challenges
of
aggregation
which
are
pathological
hallmark
aging
critically
responsible
for
a
wide
spectrum
rising
human
diseases.
Here
we
combine
joint-venture
complementary
wet-lab
experiment
molecular
simulation
to
discern
potential
ability
adenosine
triphosphate
(ATP)
as
solubilizer
protein
aggregates.
We
show
that
ATP
prevents
both
condensation
aggregation-prone
intrinsically
disordered
Aβ40
promotes
dissolution
pre-formed
Computer
links
ATP’s
solubilizing
role
its
modulate
protein’s
structural
plasticity
by
unwinding
conformation.
is
positioned
superior
biological
aggregates
over
traditional
chemical
hydrotropes,
potentially
holding
promises
therapeutic
interventions
protein-aggregation
related
Going
beyond
conventional
activity
energy
currency,
amphiphilic
nature
enables
protein-specific
interaction
would
enhance
efficiency
processes.