Exploration of Degrons and Their Ability to Mediate Targeted Protein Degradation
RSC Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
Degrons
are
regions
of
a
protein
that
required
to
initiate
their
degradation
by
cellular
machinery.
Язык: Английский
Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease
Frontiers in Cell and Developmental Biology,
Год журнала:
2025,
Номер
12
Опубликована: Фев. 7, 2025
Neurodegenerative
diseases
are
characterized
by
the
progressive
breakdown
of
neuronal
structure
and
function
pathological
accumulation
misfolded
protein
aggregates
toxic
oligomers.
A
major
contributor
to
deterioration
physiology
is
disruption
catabolic
pathways
mediated
proteasome,
a
large
protease
complex
responsible
for
most
cellular
degradation.
Previously,
it
was
believed
that
proteolysis
proteasome
required
tagging
targets
with
polyubiquitin
chains,
pathway
called
ubiquitin-proteasome
system
(UPS).
Because
this,
research
on
proteasomal
roles
in
neurodegeneration
has
historically
focused
UPS.
However,
additional
ubiquitin-independent
their
importance
increasingly
recognized.
In
this
review,
we
discuss
range
pathways,
focusing
substrate
identification
targeting,
regulatory
molecules
adaptors,
activators
alternative
caps,
diverse
complexes
including
20S
membrane
immunoproteasome,
extracellular
proteasomes,
hybrid
proteasomes.
These
further
discussed
context
aging,
oxidative
stress,
aggregation,
age-associated
neurodegenerative
diseases,
special
focus
Alzheimer's
Disease,
Huntington's
Parkinson's
Disease.
mechanistic
understanding
regulation
critical
development
therapies
treat
these
devastating
conditions.
This
review
summarizes
current
state
neurodegeneration.
Язык: Английский
ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation
Journal of Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 19, 2025
The
development
of
targeted
protein
degradation
by
recruiting
a
interest
to
ubiquitin
ligase
facilitate
its
has
become
powerful
therapeutic
tool.
potential
this
approach
is
limited
proteins
that
can
be
readily
ubiquitinated
and
relies
on
having
ligand
with
the
various
E3
ligases.
Here,
we
describe
new
methodology
for
directly
recruits
proteasome
degradation.
We
generated
bifunctional
molecules
incorporate
small
molecule
into
subunit
26S
ByeTAC
requires
binding
Rpn-13,
nonessential
receptor
proteasome,
does
not
have
rely
E
cascade
ubiquitination.
demonstrates
application
via
interactions
Rpn-13
Язык: Английский