bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Jan. 2, 2024
The
Nuclear
Pore
Complex
(NPC)
facilitates
rapid
and
selective
nucleocytoplasmic
transport
of
molecules
as
large
ribosomal
subunits
viral
capsids.
It
is
not
clear
how
key
emergent
properties
this
arise
from
the
system
components
their
interactions.
To
address
question,
we
constructed
an
integrative
coarse-grained
Brownian
dynamics
model
through
a
single
NPC,
followed
by
coupling
it
with
kinetic
Ran-dependent
in
entire
cell.
microscopic
parameters
were
fitted
to
reflect
experimental
data
theoretical
information
regarding
transport,
without
making
any
assumptions
about
its
properties.
resulting
reductionist
validated
reproducing
several
features
used
for
construction,
such
morphology
central
transporter,
rates
passive
facilitated
diffusion
function
size
valency,
situ
radial
distributions
pre-ribosomal
subunits,
active
suggests
that
NPC
functions
essentially
virtual
gate
whose
flexible
phenylalanine-glycine
(FG)
repeat
proteins
raise
entropy
barrier
pore.
Importantly,
core
functionality
greatly
enhanced
design
features,
including
'fuzzy'
transient
interactions,
multivalency,
redundancy
copy
number
FG
nucleoporins,
exponential
kinetics
thermodynamics
accordance
transition
state
theory,
energy-reliant
RanGTP
concentration
gradient.
These
result
robust
resilient
rate
selectivity
wide
array
cargo
ranging
few
kilodaltons
megadaltons
size.
By
dissecting
these
our
provides
quantitative
starting
point
rationally
modulating
artificial
mimics.
Nature,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Jan. 24, 2024
Abstract
HIV
can
infect
non-dividing
cells
because
the
viral
capsid
overcome
selective
barrier
of
nuclear
pore
complex
and
deliver
genome
directly
into
nucleus
1,2
.
Remarkably,
intact
is
more
than
1,000
times
larger
size
limit
prescribed
by
diffusion
3
This
in
central
channel
composed
intrinsically
disordered
nucleoporin
domains
enriched
phenylalanine–glycine
(FG)
dipeptides.
Through
multivalent
FG
interactions,
cellular
karyopherins
their
bound
cargoes
solubilize
this
phase
to
drive
nucleocytoplasmic
transport
4
By
performing
an
vitro
dissection
complex,
we
show
that
a
pocket
on
surface
similarly
interacts
with
motifs
from
multiple
nucleoporins
interaction
licences
capsids
penetrate
FG-nucleoporin
condensates.
karyopherin
mimicry
model
addresses
key
conceptual
challenge
for
role
entry
offers
explanation
as
how
exogenous
entity
much
any
known
cargo
may
be
able
non-destructively
breach
envelope.
Proceedings of the National Academy of Sciences,
Journal Year:
2024,
Volume and Issue:
121(4)
Published: Jan. 19, 2024
Nuclear
import
and
uncoating
of
the
viral
capsid
are
critical
steps
in
HIV-1
life
cycle
that
serve
to
transport
release
genomic
material
into
nucleus.
Viral
core
involves
translocating
at
nuclear
pore
complex
(NPC).
Notably,
central
channel
NPC
appears
often
accommodate
allow
passage
intact
capsid,
though
mechanistic
details
process
remain
be
fully
understood.
Here,
we
investigate
molecular
interactions
operate
concert
between
regulate
translocation
through
channel.
To
this
end,
develop
a
“bottom-up”
coarse-grained
(CG)
model
human
from
recently
released
cryo-electron
tomography
structure
then
construct
composite
membrane-embedded
CG
models.
We
find
successful
cytoplasmic
side
is
contingent
on
compatibility
morphology
dimension
proper
orientation
approach
side.
The
dynamics
driven
by
maximizing
contacts
phenylalanine-glycine
nucleoporins
capsid.
For
docked
capsids,
structural
analysis
reveals
correlated
striated
patterns
lattice
disorder
likely
related
intrinsic
elasticity.
Uncondensed
inside
augments
overall
Our
results
suggest
“elasticity”
can
also
aid
adapt
stress
structurally
during
translocation.
Cell,
Journal Year:
2024,
Volume and Issue:
187(3), P. 545 - 562
Published: Feb. 1, 2024
Determining
the
structure
and
mechanisms
of
all
individual
functional
modules
cells
at
high
molecular
detail
has
often
been
seen
as
equal
to
understanding
how
work.
Recent
technical
advances
have
led
a
flush
high-resolution
structures
various
macromolecular
machines,
but
despite
this
wealth
detailed
information,
our
cellular
function
remains
incomplete.
Here,
we
discuss
present-day
limitations
structural
biology
highlight
novel
technologies
that
may
enable
us
analyze
functions
directly
inside
cells.
We
predict
progression
toward
cell
will
involve
shift
conceptualizing
4D
virtual
reality
using
digital
twins.
These
capture
segments
in
highly
enriched
detail,
include
dynamic
changes,
facilitate
simulations
processes,
leading
experimentally
testable
predictions.
Transferring
biological
questions
into
algorithms
learn
from
existing
data
explore
solutions
ultimately
unveil
Nature Communications,
Journal Year:
2023,
Volume and Issue:
14(1)
Published: Nov. 13, 2023
Biomolecular
condensates
formed
via
phase
separation
of
proteins
and
nucleic
acids
are
thought
to
be
associated
with
a
wide
range
cellular
functions
dysfunctions.
We
dissect
critical
molecular
events
an
intrinsically
disordered
prion-like
low-complexity
domain
Fused
in
Sarcoma
by
performing
single-molecule
studies
permitting
us
access
the
wealth
information
that
is
skewed
conventional
ensemble
experiments.
Our
FRET
experiments
reveal
coexistence
two
conformationally
distinct
subpopulations
monomeric
form.
Single-droplet
coupled
fluorescence
correlation
spectroscopy,
picosecond
time-resolved
anisotropy,
vibrational
Raman
spectroscopy
indicate
structural
unwinding
switches
intramolecular
interactions
into
intermolecular
contacts
allowing
formation
dynamic
network
within
condensates.
A
disease-related
mutation
introduces
enhanced
plasticity
engendering
greater
interchain
can
accelerate
pathological
aggregation.
findings
provide
key
mechanistic
underpinnings
sequence-encoded
dynamically-controlled
unzipping
resulting
biological
separation.
ACS Macro Letters,
Journal Year:
2023,
Volume and Issue:
12(11), P. 1472 - 1478
Published: Oct. 19, 2023
Polymer
models
serve
as
useful
tools
for
studying
the
formation
and
physical
properties
of
biomolecular
condensates.
In
recent
years,
interface
dividing
dense
dilute
phases
condensates
has
been
discovered
to
be
closely
related
their
functionality,
but
conformational
preferences
constituent
proteins
remain
unclear.
To
elucidate
this,
we
perform
molecular
simulations
a
droplet
formed
by
phase
separation
homopolymers
surrogate
model
prion-like
low-complexity
domains.
By
systematically
analyzing
polymer
conformations
at
different
locations
in
droplet,
find
that
chains
become
compact
compared
with
interior.
Further,
segmental
analysis
revealed
end
sections
are
enriched
maximize
entropy
more
expanded
than
middle
chains.
We
majority
chain
segments
lie
tangential
surface,
only
ends
tend
align
perpendicular
interface.
These
trends
also
hold
natural
FUS
LC
LAF-1
RGG,
which
exhibit
Our
findings
provide
important
insights
into
interfacial
highlight
value
using
simple
physics
understand
underlying
mechanisms.
Chemical Reviews,
Journal Year:
2024,
Volume and Issue:
124(18), P. 10281 - 10362
Published: Aug. 9, 2024
Over
500
natural
and
synthetic
amino
acids
have
been
genetically
encoded
in
the
last
two
decades.
Incorporating
these
noncanonical
into
proteins
enables
many
powerful
applications,
ranging
from
basic
research
to
biotechnology,
materials
science,
medicine.
However,
major
challenges
remain
unleash
full
potential
of
genetic
code
expansion
across
disciplines.
Here,
we
provide
an
overview
diverse
methodologies
systems
their
final
applications
prokaryotes
eukaryotes,
represented
by
Molecular Neurodegeneration,
Journal Year:
2024,
Volume and Issue:
19(1)
Published: Jan. 22, 2024
Amyotrophic
lateral
sclerosis
(ALS)
and
frontotemporal
dementia
(FTD)
are
fatal
neurodegenerative
disorders
on
a
disease
spectrum
that
characterized
by
the
cytoplasmic
mislocalization
aberrant
phase
transitions
of
prion-like
RNA-binding
proteins
(RBPs).
The
common
accumulation
TAR
DNA-binding
protein-43
(TDP-43),
fused
in
sarcoma
(FUS),
other
nuclear
RBPs
detergent-insoluble
aggregates
cytoplasm
degenerating
neurons
ALS/FTD
is
connected
to
pore
dysfunction
defects
nucleocytoplasmic
transport
machinery.
Recent
advances
suggest
beyond
their
canonical
role
import
protein
cargoes,
nuclear-import
receptors
(NIRs)
can
prevent
reverse
TDP-43,
FUS,
related
restore
localization
function.
Here,
we
showcase
NIR
family
how
they
recognize
cargo,
drive
import,
chaperone
linked
ALS/FTD.
We
also
discuss
promise
enhancing
levels
developing
potentiated
variants
as
therapeutic
strategies
for
proteinopathies.