International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(24), С. 13693 - 13693
Опубликована: Дек. 21, 2024
Cancer
is
among
the
leading
causes
of
mortality
in
developed
countries
due
to
limited
available
therapeutic
modalities
and
high
rate
morbidity.
Although
malignancies
might
show
individual
genetic
landscapes,
recurring
aberrations
neoplastic
genome
have
been
identified
wide
range
transformed
cells.
These
include
translocations
frequently
affected
loci
human
material
like
Ewing
sarcoma
breakpoint
region
1
(EWSR1)
chromosome
22
that
results
with
mesodermal
origin.
cytogenetic
defects
result
genesis
fusion
genes
involving
EWSR1
a
number
from
partner
loci.
One
these
chromosomal
rearrangements
reciprocal
translocation
between
q13
q12
12
22,
respectively,
believed
initiate
cancer
formation
by
novel,
chimeric
transcription
factor
provoking
dysregulated
gene
expression.
Since
soft-tissue
neoplasms
carrying
t(12;22)(q13;q12)
very
poor
prognosis
clinical
specifically
targeting
t(12;22)(q13;q12)-harboring
cells
are
not
date,
understanding
this
DNA
aberration
only
timely
but
urgent.
Here,
we
review
our
current
knowledge
specific
subset
leads
expression
EWSR1::ATF1
tumor-driver
protein.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Фев. 7, 2024
Abstract
Prion-like
domains
(PLDs)
are
low-complexity
protein
sequences
enriched
within
nucleic
acid-binding
proteins
including
those
involved
in
transcription
and
RNA
processing.
PLDs
of
FUS
EWSR1
play
key
roles
recruiting
chromatin
remodeler
mammalian
SWI/SNF
(mSWI/SNF)
complex
to
oncogenic
FET
fusion
condensates.
Here,
we
show
that
disordered
multiple
subunits
prion-like
with
a
strong
propensity
undergo
intracellular
phase
separation.
These
engage
sequence-specific
heterotypic
interactions
the
PLD
dilute
at
sub-saturation
conditions,
leading
formation
co-condensates.
In
dense
phase,
homotypic
highly
cooperative,
resulting
co-mixing
individual
phases
forming
spatially
homogeneous
Heterotypic
PLD-mediated
positive
cooperativity
protein-protein
interaction
networks
is
likely
co-phase
separation
mSWI/SNF
factors
containing
homologous
domains.
The Journal of Physical Chemistry Letters,
Год журнала:
2024,
Номер
15(32), С. 8248 - 8256
Опубликована: Авг. 6, 2024
Conformational
properties
of
intrinsically
disordered
proteins
(IDPs)
are
governed
by
a
sequence-ensemble
relationship.
To
differentiate
the
impact
sequence-local
versus
sequence-nonlocal
features
an
IDP's
charge
pattern
on
its
conformational
dimensions
and
phase-separation
propensity,
"blockiness"
κ
nonlocality-weighted
sequence
decoration
(SCD)
parameters
compared
for
their
correlations
with
isolated-chain
radii
gyration
(Rgs)
upper
critical
solution
temperatures
(UCSTs)
polyampholytes
modeled
random
phase
approximation,
field-theoretic
simulation,
coarse-grained
molecular
dynamics.
SCD
is
superior
to
in
predicting
Rg
because
accounts
effects
contact
order,
i.e.,
nonlocality,
isolated
chains.
In
contrast,
comparably
good,
though
nonideal,
predictors
UCST
frequencies
interchain
contacts
multiple-chain
condensed
less
sensitive
positions
than
intrachain
chain,
as
reflected
correlating
better
condensed-phase
interaction
energy
SCD.
PLoS Computational Biology,
Год журнала:
2025,
Номер
21(1), С. e1012737 - e1012737
Опубликована: Янв. 13, 2025
Intracellular
liquid–liquid
phase
separation
(LLPS)
of
proteins
and
nucleic
acids
is
a
fundamental
mechanism
by
which
cells
compartmentalize
their
components
perform
essential
biological
functions.
Molecular
simulations
play
crucial
role
in
providing
microscopic
insights
into
the
physicochemical
processes
driving
this
phenomenon.
In
study,
we
systematically
compare
six
state-of-the-art
sequence-dependent
residue-resolution
models
to
evaluate
performance
reproducing
behaviour
material
properties
condensates
formed
seven
variants
low-complexity
domain
(LCD)
hnRNPA1
protein
(A1-LCD)—a
implicated
pathological
liquid-to-solid
transition
stress
granules.
Specifically,
assess
HPS,
HPS-cation–
π
,
HPS-Urry,
CALVADOS2,
Mpipi,
Mpipi-Recharged
predictions
condensate
saturation
concentration,
critical
solution
temperature,
viscosity
A1-LCD
variants.
Our
analyses
demonstrate
that,
among
tested
models,
Mpipi-Recharged,
CALVADOS2
provide
accurate
descriptions
temperatures
concentrations
for
multiple
tested.
Regarding
prediction
its
variants,
stands
out
as
most
reliable
model.
Overall,
study
benchmarks
range
coarse-grained
thermodynamic
stability
establishes
direct
link
between
ranking
intermolecular
interactions
these
consider.
TAR
DNA-binding
protein
43
(TDP-43)
is
a
multidomain
involved
in
the
regulation
of
RNA
metabolism,
and
its
aggregates
have
been
observed
neurodegenerative
diseases,
including
amyotrophic
lateral
sclerosis
(ALS)
frontotemporal
dementia
(FTD).
Numerous
studies
indicate
TDP-43
can
undergo
liquid-liquid
phase
separation
(LLPS)
vitro
component
biological
condensates.
Homo-oligomerization
via
folded
N-terminal
domain
(aa:1-77)
conserved
helical
region
(aa:319-341)
disordered,
C-terminal
found
to
be
an
important
driver
separation.
However,
comprehensive
molecular
view
separation,
particularly
regarding
nature
heterodomain
interactions,
lacking
due
challenges
associated
with
stability
purification.
Here,
we
utilize
all-atom
coarse-grained
(CG)
dynamics
(MD)
simulations
uncover
network
interdomain
interactions
implicated
All-atom
uncovered
presence
transient,
involving
flexible
linkers,
RNA-recognition
motif
(RRM)
domains
charged
segment
disordered
(CTD).
CG
these
inter-domain
which
affect
conformational
landscape
dilute
are
also
prevalent
condensed
phase.
Finally,
sequence
surface
charge
distribution
analysis
coupled
(at
high
salt)
confirmed
that
transient
contacts
predominantly
electrostatic
nature.
Overall,
our
findings
from
multiscale
lead
greater
appreciation
complex
interaction
underlying
structural
TDP-43.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 6, 2024
Abstract
The
primarily
disordered
C-terminal
domain
(CTD)
of
TAR
DNA
binding
protein-43
(TDP-43),
a
key
nuclear
protein
in
RNA
metabolism,
forms
neuronal
inclusions
several
neurodegenerative
diseases.
A
conserved
region
(CR,
spanning
residues
319-341)
CTD
transient
helix-helix
contacts
important
for
its
higher-order
oligomerization
and
function
that
are
disrupted
by
ALS-associated
mutations.
However,
the
structural
details
CR
assembly
explanation
variants’
impact
on
phase
separation
remain
unclear
due
to
challenges
analyzing
dynamic
association
TDP-43
using
traditional
biology
approaches.
By
employing
an
integrative
approach,
combining
biophysical
experiments,
biochemical
assays,
AlphaFold2-Multimer
(AF2-Multimer),
atomistic
simulations,
we
generated
models
helical
CR.
Using
NMR,
first
established
native
state
under
physiological
conditions
is
α-helical.
Next,
alanine
scanning
mutagenesis
revealed
while
hydrophobic
assembly,
retention
function,
polar
down
regulate
these
processes.
Finally,
pairing
AF2-Multimer
modeling
with
AAMD
simulations
indicated
dynamic,
oligomeric
assemblies
stabilized
methionine-rich
core
specific
contributions
from
tryptophan/leucine
pair.
In
conclusion,
our
results
advance
understanding
mechanisms
driving
provide
window
into
initial
stages
conversion
pathogenic
aggregates.
Abstract
A
molecular
grammar
governing
low-complexity
prion-like
domains
phase
separation
(PS)
has
been
proposed
based
on
mutagenesis
experiments
that
identified
tyrosine
and
arginine
as
primary
drivers
of
via
aromatic-aromatic
aromatic-arginine
interactions.
Here
we
show
additional
residues
make
direct
favorable
contacts
contribute
to
separation,
highlighting
the
need
account
for
these
contributions
in
PS
theories
models.
We
find
important
beyond
only
tyrosine-tyrosine
tyrosine-arginine,
including
arginine-arginine
contacts.
Among
polar
residues,
glutamine
particular
contributes
with
sequence/position-specificity,
making
both
well
other
before
condensed
phases.
For
glycine,
its
flexibility,
not
small
solvation
volume,
favors
by
allowing
between
inhibits
liquid-to-solid
(LST)
transition.
Polar
residue
types
also
sequence-specific
aggregation
go
simple
rules,
which
serine
positions
is
linked
formation
an
amyloid-core
structure
FUS
domain.
Hence,
here
propose
a
revised
expanding
role
domain
protein
aggregation.
F1000Research,
Год журнала:
2025,
Номер
14, С. 37 - 37
Опубликована: Янв. 6, 2025
TAF15
(TATA-box
binding
protein-associated
factor
15)
is
a
member
of
the
FET
protein
family,
known
for
their
roles
in
transcriptional
regulation
and
RNA
metabolism.
Here
we
have
characterized
five
TAF15
commercial
antibodies
western
blot,
immunoprecipitation,
immunofluorescence
using
standardized
experimental
protocol
based
on
comparing
read-outs
knockout
cell
lines
isogenic
parental
controls.
These
studies
are
part
larger,
collaborative
initiative
seeking
to
address
antibody
reproducibility
issues
by
characterizing
commercially
available
human
proteins
publishing
results
openly
as
resource
scientific
community.
While
use
protocols
vary
between
laboratories,
encourage
readers
this
report
guide
select
most
appropriate
specific
needs.