Cell Stress and Chaperones,
Год журнала:
2023,
Номер
28(6), С. 631 - 640
Опубликована: Сен. 20, 2023
Protein
quality
control
pathways
ensure
a
functional
proteome
and
rely
on
complex
proteostasis
network
(PN)
that
is
composed
of
molecular
chaperones
proteases.
Failures
in
the
PN
can
lead
to
broad
spectrum
diseases,
including
neurodegenerative
disorders
like
Alzheimer's,
Parkinson's,
range
motor
neuron
diseases.
The
EMBO
workshop
"Protein
control:
from
mechanisms
therapeutic
intervention"
covered
all
aspects
protein
underlying
proteases
stress
signaling
medical
implications.
This
report
summarizes
highlights
selected
presentations.
Trends in Biochemical Sciences,
Год журнала:
2023,
Номер
49(2), С. 105 - 118
Опубликована: Ноя. 1, 2023
Ribosomes
interact
with
a
variety
of
different
protein
biogenesis
factors
that
guide
newly
synthesized
proteins
to
their
native
3D
shapes
and
cellular
localization.
Depending
on
the
type
translated
substrate,
distinct
set
cotranslational
must
ribosome
in
timely
coordinated
manner
ensure
proper
biogenesis.
While
cytonuclear
require
maturation
folding
factors,
secretory
be
maintained
an
unfolded
state
processed
cotranslationally
by
transport
membrane
translocation
factors.
Here
we
explore
specific
processing
steps
for
cytonuclear,
secretory,
eukaryotes
then
discuss
how
nascent
polypeptide-associated
complex
(NAC)
sorts
these
into
correct
pathway.
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(39)
Опубликована: Сен. 12, 2024
An
N-degron
is
a
degradation
signal
whose
main
determinant
“destabilizing”
N-terminal
residue
of
protein.
Specific
N-degrons,
discovered
in
1986,
were
the
first
identified
signals
short-lived
intracellular
proteins.
These
N-degrons
are
recognized
by
ubiquitin-dependent
proteolytic
system
called
Arg/N-degron
pathway.
Although
bacteria
lack
ubiquitin
system,
they
also
have
pathways.
Studies
after
1986
shown
that
all
20
amino
acids
genetic
code
can
act,
specific
sequence
contexts,
as
destabilizing
residues.
Eukaryotic
proteins
targeted
for
conditional
or
constitutive
at
least
five
systems
differ
both
functionally
and
mechanistically:
pathway,
Ac/N-degron
Pro/N-degron
fMet/N-degron
newly
named,
this
perspective,
GASTC/N-degron
pathway
(GASTC
=
Gly,
Ala,
Ser,
Thr,
Cys).
I
discuss
these
expanded
terminology
now
encompasses
entire
gamut
known
Trends in Biochemical Sciences,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
The
majority
of
eukaryotic
proteins
undergo
N-terminal
(Nt)
modifications
facilitated
by
various
enzymes.
These
enzymes,
which
target
the
initial
amino
acid
a
polypeptide
in
sequence-dependent
manner,
encompass
peptidases,
transferases,
cysteine
oxygenases,
and
ligases.
Nt
-
such
as
acetylation,
fatty
acylations,
methylation,
arginylation,
oxidation
enhance
proteome
complexity
regulate
protein
targeting,
stability,
complex
formation.
Modifications
at
N
termini
are
thereby
core
components
large
number
biological
processes,
including
cell
signaling
motility,
autophagy
regulation,
plant
animal
oxygen
sensing.
Dysregulation
Nt-modifying
enzymes
is
implicated
several
human
diseases.
In
this
feature
review
we
provide
an
overview
occurring
either
co-
or
post-translationally,
involved,
impact.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Фев. 3, 2025
Eukaryotic
translation
elongation
factor
1A
(eEF1A)
is
a
highly
abundant,
multi-domain
GTPase.
Post-translational
steps
essential
for
eEF1A
biogenesis
are
carried
out
by
bespoke
chaperones
but
co-translational
mechanisms
tailored
to
folding
remain
unexplored.
Here,
we
use
AlphaPulldown
identify
Ypl225w
(also
known
as
Chp1,
Chaperone
1
eEF1A)
conserved
yeast
protein
predicted
stabilize
the
N-terminal,
GTP-binding
(G)
domain
of
against
its
misfolding
propensity,
computational
simulations
and
validated
microscopy
analysis
ypl225wΔ
cells.
Proteomics
biochemical
reconstitution
reveal
that
functions
chaperone
forming
dual
interactions
with
G
nascent
chain
UBA
ribosome-bound
polypeptide-associated
complex
(NAC).
Lastly,
show
primes
chains
binding
GTP
part
mechanism
tightly
coupled
recycling.
Our
work
shows
an
ATP-independent
can
drive
vectorial
co-opting
nucleotide
binding.
Folding
proteins
begin
during
their
synthesis.
Sabbarini
et
al.
(Chp1)
role
NAC
in
process
recruitment
factor.
Molecular Cell,
Год журнала:
2024,
Номер
84(6), С. 1101 - 1119.e9
Опубликована: Фев. 29, 2024
Mitochondrial
outer
membrane
⍺-helical
proteins
play
critical
roles
in
mitochondrial-cytoplasmic
communication,
but
the
rules
governing
targeting
and
insertion
of
these
biophysically
diverse
remain
unknown.
Here,
we
first
defined
complement
required
mammalian
biogenesis
machinery
through
genome-wide
CRISPRi
screens
using
topologically
distinct
proteins.
Systematic
analysis
nine
identified
factors
across
21
substrates
reveals
that
components
are
organized
into
pathways
act
on
based
their
topology.
NAC
is
for
efficient
polytopic
proteins,
whereas
signal-anchored
require
TTC1,
a
cytosolic
chaperone
physically
engages
substrates.
Biochemical
mutational
studies
reveal
TTC1
employs
conserved
TPR
domain
hydrophobic
groove
its
C-terminal
to
support
substrate
solubilization
mitochondria.
Thus,
mitochondrial
achieved
topological
triaging
cytosol
principles
with
similarities
ER
protein
systems.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Янв. 24, 2024
Excision
of
the
initiator
methionine
is
among
first
co-translational
processes
that
occur
at
ribosome.
While
this
crucial
step
in
protein
maturation
executed
by
two
types
aminopeptidases
eukaryotes
(MAP1
and
MAP2),
additional
roles
disease
translational
regulation
have
drawn
more
attention
to
MAP2.
Here,
we
report
several
cryo-EM
structures
human
fungal
MAP2
80S
Irrespective
nascent
chains,
can
occupy
tunnel
exit.
On
chain
displaying
ribosomes,
MAP2-80S
interaction
highly
dynamic
MAP2-specific
N-terminal
extension
engages
stabilizing
interactions
with
long
rRNA
expansion
segment
ES27L.
Loss
autoproteolytic
cleavage
impedes
tunnel,
while
promoting
enter
ribosomal
A-site,
where
it
functional
centers
translation.
These
findings
reveal
proteolytic
remodeling
severely
affects
ribosome
binding,
set
stage
for
targeted
studies.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Сен. 3, 2024
Abstract
Nascent
chains
undergo
co-translational
enzymatic
processing
as
soon
their
N-terminus
becomes
accessible
at
the
ribosomal
polypeptide
tunnel
exit
(PTE).
In
eukaryotes,
N-terminal
methionine
excision
(NME)
by
Methionine
Aminopeptidases
(MAP1
and
MAP2),
acetylation
(NTA)
N-Acetyl-Transferase
A
(NatA),
is
most
common
combination
of
subsequent
modifications
carried
out
on
80S
ribosome.
How
these
processes
are
coordinated
in
context
a
rapidly
translating
ribosome
has
remained
elusive.
Here,
we
report
two
cryo-EM
structures
multi-enzyme
complexes
assembled
vacant
human
ribosomes,
indicating
routes
for
NME-NTA.
Both
assemblies
form
independent
nascent
chain
substrates.
Irrespective
route,
NatA
occupies
non-intrusive
‘distal’
binding
site
which
does
not
interfere
with
MAP1
or
MAP2
nor
other
ribosome-associated
factors
(RAFs).
can
partake
coordinated,
dynamic
assembly
through
hydra-like
chaperoning
function
abundant
Polypeptide-Associated
Complex
(NAC).
contrast
to
MAP1,
completely
covers
PTE
thus
incompatible
NAC
recruitment.
Together,
our
data
provide
structural
framework
orchestration
NME
NTA
protein
biogenesis.
