bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 31, 2025
Abstract
Citropin
1.3
is
an
antimicrobial
peptide
produced
by
the
amphibian
Litoria
citropa
(Southern
bell
frog),
which
self-aggregates
into
distinct
fibrillar
structures,
however,
function
of
fibrils
remains
unclear
and
largely
unexplored.
In
this
study,
structural
functional
properties
citropin
were
investigated
using
cryogenic
electron
microscopy
fluorescence
in
presence
membrane
cell
models,
with
X-ray
crystallography.
Canonical
amyloids,
multilayered
nanotubes,
a
novel
mixed
fibril
observed.
Experiments
negatively
charged
giant
unilamellar
vesicles
revealed
that
facilitates
fusion
while
simultaneously
undergoing
phase
separation
phospholipids.
mammalian
cells,
permeabilizes
membranes,
leading
to
death,
over
time,
colocalizes
genetic
material.
Overall,
work
provides
new
insights
dynamics
amyloidogenic
its
interactions
different
systems.
Abundant
filamentous
inclusions
of
tau
are
characteristic
more
than
20
neurodegenerative
diseases
that
collectively
termed
tauopathies.
Electron
cryo-microscopy
(cryo-EM)
structures
amyloid
filaments
from
human
brain
revealed
distinct
folds
characterise
many
different
diseases.
A
lack
laboratory-based
model
systems
to
generate
these
has
hampered
efforts
uncover
the
molecular
mechanisms
underlie
Here,
we
report
in
vitro
assembly
conditions
with
recombinant
replicate
both
Alzheimer's
disease
(AD)
and
chronic
traumatic
encephalopathy
(CTE),
as
determined
by
cryo-EM.
Our
results
suggest
post-translational
modifications
modulate
filament
assembly,
previously
observed
additional
densities
AD
CTE
may
arise
presence
inorganic
salts,
like
phosphates
sodium
chloride.
In
into
disease-relevant
will
facilitate
studies
determine
their
roles
diseases,
well
development
compounds
specifically
bind
or
prevent
formation.
Nature,
Journal Year:
2023,
Volume and Issue:
625(7993), P. 119 - 125
Published: Nov. 29, 2023
Abstract
Intermediate
species
in
the
assembly
of
amyloid
filaments
are
believed
to
play
a
central
role
neurodegenerative
diseases
and
may
constitute
important
targets
for
therapeutic
intervention
1,2
.
However,
structural
information
about
intermediate
has
been
scarce
molecular
mechanisms
by
which
amyloids
assemble
remain
largely
unknown.
Here
we
use
time-resolved
cryogenic
electron
microscopy
study
vitro
recombinant
truncated
tau
(amino
acid
residues
297–391)
into
paired
helical
Alzheimer’s
disease
or
chronic
traumatic
encephalopathy
3
We
report
formation
shared
first
filament,
with
an
ordered
core
comprising
302–316.
Nuclear
magnetic
resonance
indicates
that
same
adopt
rigid,
β-strand-like
conformations
monomeric
tau.
At
later
time
points,
disappears
observe
many
different
filaments,
structures
depend
on
reaction
conditions.
end
both
reactions,
most
disappear
cores
as
those
from
human
brains
remain.
Our
results
provide
insights
processes
primary
secondary
nucleation
assembly,
implications
design
new
therapies.
PLoS Pathogens,
Journal Year:
2022,
Volume and Issue:
18(11), P. e1010947 - e1010947
Published: Nov. 7, 2022
Prion
strains
in
a
given
type
of
mammalian
host
are
distinguished
by
differences
clinical
presentation,
neuropathological
lesions,
survival
time,
and
characteristics
the
infecting
prion
protein
(PrP)
assemblies.
Near-atomic
structures
prions
from
two
species
with
different
PrP
sequences
have
been
determined
but
comparisons
distinct
same
amino
acid
sequence
needed
to
identify
purely
conformational
determinants
strain
characteristics.
Here
we
report
3.2
Å
resolution
cryogenic
electron
microscopy-based
structure
22L
purified
brains
mice
engineered
express
only
lacking
glycophosphatidylinositol
anchors
[anchorless
(a)
22L].
Comparison
this
near-atomic
our
recently
aRML
propagated
inbred
mouse
reveals
that
these
templates
for
growth
via
incorporation
molecules
sequence.
Both
a22L
assembled
as
stacks
forming
parallel
in-register
intermolecular
β-sheets
intervening
loops,
single
monomers
spanning
ordered
fibril
core.
Each
monomer
shares
an
N-terminal
steric
zipper,
three
major
arches,
overall
V-shape,
details
other
features
differ
markedly.
Thus,
variations
shared
motifs
within
β-stack
architecture
provide
structural
basis
differentiation
genotype.
Proceedings of the National Academy of Sciences,
Journal Year:
2025,
Volume and Issue:
122(5)
Published: Jan. 28, 2025
The
formation
of
superoxide
dismutase
1
(SOD1)
filaments
has
been
implicated
in
amyotrophic
lateral
sclerosis
(ALS).
Although
the
disulfide
bond
formed
between
Cys57
and
Cys146
active
state
well
studied,
role
reduced
cysteine
residues,
Cys6
Cys111,
SOD1
filament
remains
unclear.
In
this
study,
we
investigated
residues
by
determining
comparing
cryoelectron
microscopy
(cryo-EM)
structures
wild-type
(WT)
C6A/C111A
under
thiol-based
reducing
metal-depriving
conditions,
starting
with
protein
samples
possessing
enzymatic
activity.
mutant
more
rapidly
than
WT
protein.
structure
had
a
unique
paired-protofilament
arrangement,
smaller
core
that
single-protofilament
observed
SOD1.
form
developed
slowly,
cross-seeding
experiments
demonstrated
predominance
morphology
over
paired
protofilaments,
regardless
presence
Cys111
mutations.
These
findings
highlight
importance
number
amino
acid
within
energy
requirements
for
assembly.
Our
study
provides
insights
into
ALS
pathogenesis
elucidating
initiation
propagation
formation,
which
potentially
leads
to
deleterious
amyloid
filaments.
International Journal of Molecular Sciences,
Journal Year:
2023,
Volume and Issue:
24(6), P. 5383 - 5383
Published: March 11, 2023
Alzheimer’s
disease
(AD)
is
an
incurable,
progressive
neurodegenerative
disorder.
AD
a
complex
and
multifactorial
that
responsible
for
60–80%
of
dementia
cases.
Aging,
genetic
factors,
epigenetic
changes
are
the
main
risk
factors
AD.
Two
aggregation-prone
proteins
play
decisive
role
in
pathogenesis:
β-amyloid
(Aβ)
hyperphosphorylated
tau
(pTau).
Both
them
form
deposits
diffusible
toxic
aggregates
brain.
These
biomarkers
Different
hypotheses
have
tried
to
explain
pathogenesis
served
as
platforms
drug
research.
Experiments
demonstrated
both
Aβ
pTau
might
start
processes
necessary
cognitive
decline.
The
two
pathologies
act
synergy.
Inhibition
formation
has
been
old
target.
Recently,
successful
clearance
by
monoclonal
antibodies
raised
new
hopes
treatments
if
detected
at
early
stages.
More
recently,
novel
targets,
e.g.,
improvements
amyloid
from
brain,
application
small
heat
shock
(Hsps),
modulation
chronic
neuroinflammation
different
receptor
ligands,
microglial
phagocytosis,
increase
myelination
revealed
Proceedings of the National Academy of Sciences,
Journal Year:
2023,
Volume and Issue:
120(44)
Published: Oct. 25, 2023
The
microtubule-associated
protein
tau
aggregates
into
neurofibrillary
tangles
in
Alzheimer’s
disease
(AD).
main
type
of
aggregates,
the
paired
helical
filaments
(PHF),
incorporate
about
20%
full-length
rigid
core.
Recently,
cryo-electron
microscopy
data
showed
that
a
protease-resistant
fragment
(residues
297–391)
self-assembles
vitro
presence
divalent
cations
to
form
twisted
whose
molecular
structure
resembles
AD
PHF
[S.
Lövestam
et
al.,
Elife
11
,
e76494
(2022)].
To
investigate
whether
this
construct
is
uniquely
predisposed
morphology
and
structure,
we
fibrillized
(297–391)
under
reported
conditions
determined
its
using
solid-state
NMR
spectroscopy.
Unexpectedly,
assembled
predominantly
nontwisting
ribbons
core
spans
residues
305–357.
This
forms
β-arch
turns
at
322
CGS
324
.
Two
protofilaments
stack
together
via
long
interface
stretches
from
G323
I354.
Together,
these
two
four-layered
β-sheet
sidechains
are
stabilized
by
numerous
polar
hydrophobic
interactions.
gives
insight
fibril
morphologies
conformations
can
be
adopted
different
pH
ionic
conditions.
Acta Neuropathologica,
Journal Year:
2024,
Volume and Issue:
148(1)
Published: Oct. 24, 2024
Chronic
wasting
disease
(CWD)
is
a
widely
distributed
prion
of
cervids
with
implications
for
wildlife
conservation
and
also
human
livestock
health.
The
structures
infectious
prions
that
cause
CWD
other
natural
diseases
mammalian
hosts
have
been
poorly
understood.
Here
we
report
2.8
Å
resolution
cryogenic
electron
microscopy-based
structure
fibrils
from
the
brain
naturally
infected
white-tailed
deer
expressing
most
common
wild-type
PrP
sequence.
Like
recently
solved
rodent-adapted
scrapie
fibrils,
our
atomic
model
contains
single
stacks
molecules
forming
parallel
in-register
intermolecular
β-sheets
intervening
loops
comprising
major
N-
C-terminal
lobes
within
fibril
cross-section.
However,
cervid
host
differ
markedly
rodent
in
many
features,
including
~
180°
twist
relative
orientation
lobes.
This
suggests
mechanisms
underlying
apparent
transmission
barrier
to
humans
should
facilitate
more
rational
approaches
development
vaccines
therapeutics.