Cell Reports,
Год журнала:
2024,
Номер
43(7), С. 114419 - 114419
Опубликована: Июль 1, 2024
The
compaction
of
chromatin
into
mitotic
chromosomes
is
essential
for
faithful
transmission
the
genome
during
cell
division.
In
eukaryotes,
chromosome
morphogenesis
regulated
by
condensin
complex,
though
exact
mechanism
used
to
target
and
initiate
condensation
not
understood.
Here,
we
reveal
that
contains
an
intrinsically
disordered
region
(IDR)
modulates
its
association
with
in
early
mitosis
exhibits
phase
separation.
We
describe
DNA-binding
motifs
within
IDR
that,
upon
deletion,
inflict
striking
defects
segregation,
ill-timed
turnover
on
chromatin,
death.
Importantly,
demonstrate
can
impart
cycle
regulatory
functions
when
transferred
other
subunits
indicating
autonomous
nature.
Collectively,
our
study
unveils
molecular
basis
initiation
how
this
process
ultimately
promotes
genomic
stability
faultless
Wiley Interdisciplinary Reviews Computational Molecular Science,
Год журнала:
2023,
Номер
13(6)
Опубликована: Авг. 26, 2023
Abstract
Intrinsically
disordered
proteins
(IDPs)
are
that
perform
important
biological
functions
without
well‐defined
structures
under
physiological
conditions.
IDPs
can
form
fuzzy
complexes
with
other
molecules,
participate
in
the
formation
of
membraneless
organelles,
and
function
as
hubs
protein–protein
interaction
networks.
The
malfunction
causes
major
human
diseases.
However,
drug
design
targeting
remains
challenging
due
to
their
highly
dynamic
interactions.
Turning
into
druggable
targets
provides
a
great
opportunity
extend
target‐space
for
novel
discovery.
Integrative
structural
biology
approaches
combine
information
derived
from
computational
simulations,
artificial
intelligence/data‐driven
analysis
experimental
studies
have
been
used
uncover
interactions
IDPs.
An
increasing
number
ligands
directly
bind
found
either
by
target‐based
screening
or
phenotypic
screening.
Along
understanding
IDP
binding
its
partners,
structure‐based
strategies,
especially
conformational
ensemble‐based
ligand
computer‐aided
optimization
algorithms,
greatly
accelerated
development
ligands.
It
is
inspiring
several
IDP‐targeting
small‐molecule
peptide
drugs
advanced
clinical
trials.
new
methods
need
be
further
developed
efficiently
discovering
optimizing
specific
potent
vast
interactions,
expected
become
valuable
treasure
targets.
This
article
categorized
under:
Structure
Mechanism
>
Computational
Biochemistry
Biophysics
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Июль 13, 2024
The
early
phases
of
clathrin
mediated
endocytosis
are
organized
through
a
highly
complex
interaction
network
by
associated
sorting
proteins
(CLASPs)
that
comprise
long
intrinsically
disordered
regions
(IDRs).
AP180
is
CLASP
exclusively
expressed
in
neurons
and
comprises
IDR
around
600
residues,
whose
function
remains
partially
elusive.
Using
NMR
spectroscopy,
we
discovered
an
extended
strong
site
within
with
the
major
adaptor
protein
AP2,
describe
its
binding
dynamics
at
atomic
resolution.
We
find
70
residue-long
determines
overall
between
AP2
dynamic
equilibrium
bound
unbound
states,
while
weaker
sites
contribute
to
affinity
much
higher
concentrations
AP2.
Our
data
suggest
this
particular
might
play
central
role
recruitment
adaptors
coated
pit,
whereas
more
transient
promiscuous
interactions
allow
reshaping
until
cargo
uptake
inside
vesicle.
Journal of Biomolecular Structure and Dynamics,
Год журнала:
2025,
Номер
unknown, С. 1 - 11
Опубликована: Фев. 12, 2025
The
TFIIS
N-terminal
domain
(TND)
is
a
crucial
protein
scaffold
that
selectively
recognizes
disordered
ligands,
known
as
TND-interacting
motifs
(TIMs).
Understanding
the
specific
mechanisms
of
TND-TIM
interactions
essential
for
deciphering
transcription
machinery.
Here,
we
investigated
conformational
ensembles
interaction
module
using
molecular
dynamics
simulations.
study
revealed
experimental
structures
complexes,
including
P75-PogZ
and
P75-IWS1,
maintained
stable
conformations
during
microsecond-long
simulations,
even
when
linked
proteins
between
TND
TIM
were
removed
or
was
phosphorylated.
Conversely,
both
P75-ASK
HRP2-IWS1,
prepared
based
on
structure
are
unstable
in
simulations;
example,
helix-1
TIMs
shifts
from
their
initial
binding
site
TND.
However,
phosphorylation
enhances
rapidly
stabilizes
complex
structure.
A
general
rule
regulation
identified:
phosphoryl
group
forms
hydrogen
bonds
with
positively
charged
side
chains
residues,
promoting
dynamic
correlation
Ser-containing
acidic
linker
TIM,
enhancing
residue-residue
among
FXGF
motif
These
phosphorylation-induced
changes
resulted
higher
affinity
TIM.
Our
provides
insights
into
phosphorylation-regulated
at
an
atomic
level,
facilitating
deeper
understanding
interactome
assembly
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 17, 2025
Summary
As
the
only
gateway
governing
nucleocytoplasmic
transport,
nuclear
pore
complex
(NPC)
maintains
fundamental
cellular
processes
and
deteriorates
with
age.
However,
study
of
age-related
roles
single
NPC
components
remains
challenging
owing
to
complexity
composition.
Here
we
demonstrate
that
master
energy
sensor,
AMPK,
post-translationally
regulates
abundance
nucleoporin
NPP-16/NUP50
in
response
nutrient
availability
energetic
stress.
In
turn,
promotes
transcriptomic
activation
lipid
catabolism
extend
lifespan
Caenorhabditis
elegans
independently
its
role
transport.
Rather,
intrinsically
disordered
region
(IDR)
NPP-16/NUP50,
through
direct
interaction
transcriptional
machinery,
transactivates
promoters
catabolic
genes.
Remarkably,
elevated
levels
are
sufficient
promote
longevity
metabolic
stress
defenses.
AMPK-NUP50
signaling
is
conserved
human,
indicating
bridging
sensing
adaptation
an
ancient
this
axis.
Biomedicines,
Год журнала:
2025,
Номер
13(3), С. 594 - 594
Опубликована: Март 1, 2025
Bromodomain
and
extra-terminal
domain
(BET)
proteins
are
epigenetic
readers
that
recognize
the
histone
acetylation
code
play
a
critical
role
in
regulating
gene
transcription.
Dysregulation
of
BET
is
associated
with
number
pathologies,
including
cancer,
inflammation-related
metabolic
disorders,
etc.
can
also
be
hijacked
by
some
viruses
mediate
latent
viral
infections,
making
promising
targets
for
therapeutic
intervention.
Research
this
area
has
mainly
focused
on
bromodomain
inhibition,
less
attention
paid
to
other
domains.
inhibitors
have
great
potential
as
anticancer
anti-inflammatory
drug
candidates.
However,
their
broad-spectrum
impact
transcription
cross-reactivity
non-BET
bromodomain-containing
raise
concerns
about
unforeseen
side
effects.
Non-bromodomain
hold
promise
gaining
better
control
over
expression
host
genes
targeting
different
stages
BET-dependent
transcriptional
regulation.
In
review,
we
discuss
recent
advances
development
non-bromodomain
inhibitors,
well
applications,
advantages,
perspectives.
Epigenetics & Chromatin,
Год журнала:
2025,
Номер
18(1)
Опубликована: Апрель 4, 2025
TIP60
is
a
crucial
lysine
acetyltransferase
protein
that
catalyzes
the
acetylation
of
histone
and
non-histone
proteins.
This
enzyme
plays
role
in
maintaining
genomic
integrity,
by
participating
DNA
damage
repair,
ensuring
accurate
chromosomal
segregation,
regulating
myriad
cellular
processes
such
as
apoptosis,
autophagy,
wound-induced
cell
migration.
One
primary
mechanisms
through
which
executes
these
diverse
functions
via
post-translational
modifications
(PTMs).
Over
years,
extensive
studies
have
demonstrated
importance
PTMs
controlling
functions.
review
aims
to
summarize
findings
on
occurring
their
functional
implications.
We
also
discuss
previously
uncharacterized
PTM
sites
identified
examine
relationship
with
cancer-associated
mutations,
particular
focus
residues
potentially
modified
various
PTMs,
understand
cause
deregulation
cancers.
