Biochemical Journal,
Год журнала:
2023,
Номер
480(10), С. 715 - 728
Опубликована: Май 19, 2023
As
sequence
and
structural
databases
grow
along
with
powerful
analysis
tools,
the
prevalence
diversity
of
pseudoenzymes
have
become
increasingly
evident.
Pseudoenzymes
are
present
across
tree
life
in
a
large
number
enzyme
families.
defined
as
proteins
that
lack
conserved
catalytic
motifs
based
on
analysis.
However,
some
may
migrated
amino
acids
necessary
for
catalysis,
allowing
them
to
catalyze
enzymatic
reactions.
Furthermore,
retain
several
non-enzymatic
functions
such
allosteric
regulation,
signal
integration,
scaffolding,
competitive
inhibition.
In
this
review,
we
provide
examples
each
mode
action
using
pseudokinase,
pseudophosphatase,
pseudo
ADP-ribosyltransferase
We
highlight
methodologies
facilitate
biochemical
functional
characterization
encourage
further
investigation
burgeoning
field.
Science Signaling,
Год журнала:
2020,
Номер
13(639)
Опубликована: Июль 7, 2020
Reactive
oxygen
species
(ROS)
are
physiological
mediators
of
cellular
signaling
and
play
potentially
damaging
roles
in
human
diseases.
In
this
study,
we
found
that
the
catalytic
activity
Ser/Thr
kinase
Aurora
A
was
inhibited
by
oxidation
a
conserved
cysteine
residue
(Cys
Redox Biology,
Год журнала:
2019,
Номер
28, С. 101318 - 101318
Опубликована: Сен. 5, 2019
Aurora
A
kinase
is
a
master
mitotic
regulator
whose
functions
are
controlled
by
several
regulatory
interactions
and
post-translational
modifications.
It
frequently
dysregulated
in
cancer,
making
inhibition
very
attractive
antitumor
target.
However,
recently
uncovered
links
between
A,
cellular
metabolism
redox
regulation
not
well
understood.
In
this
study,
we
report
novel
mechanism
of
the
response
to
oxidative
stress
through
CoAlation.
combination
biochemical,
biophysical,
crystallographic
cell
biology
approaches
revealed
new
and,
our
knowledge,
unique
mode
CoA,
involving
selective
binding
ADP
moiety
CoA
ATP
pocket
covalent
modification
Cys290
activation
loop
thiol
group
pantetheine
tail.
We
provide
evidence
that
(CoAlation)
specific,
it
can
be
induced
human
cells.
Oxidising
agents,
such
as
diamide,
hydrogen
peroxide
menadione
were
found
induce
Thr
288
phosphorylation
DTT-dependent
dimerization
A.
Moreover,
microinjection
into
fertilized
mouse
embryos
disrupts
bipolar
spindle
formation
alignment
chromosomes,
consistent
with
inhibition.
Altogether,
data
reveal
new,
rather
selective,
inhibitor
which
locks
an
inactive
state
via
"dual
anchor"
might
also
operate
stress.
Finally
most
importantly,
believe
these
findings
rationale
for
developing
effective
irreversible
inhibitors
perhaps
other
protein
kinases
containing
appropriately
conserved
Cys
residues.
FEBS Journal,
Год журнала:
2020,
Номер
287(19), С. 4150 - 4169
Опубликована: Фев. 13, 2020
Pseudoenzymes
are
present
within
many,
but
not
all,
known
enzyme
families
and
lack
one
or
more
conserved
canonical
amino
acids
that
help
define
their
catalytically
active
counterparts.
Recent
findings
in
the
pseudokinase
field
confirm
evolutionary
repurposing
of
structurally
defined
bilobal
protein
kinase
fold
permits
distinct
biological
functions
to
emerge,
many
which
rely
on
conformational
switching,
as
opposed
catalysis.
In
this
analysis,
we
evaluate
progress
evaluating
several
members
‘dark’
pseudokinome
pertinent
drive
expanding
field.
Initially,
discuss
how
adaptions
erythropoietin‐producing
hepatocellular
carcinoma
(Eph)
receptor
tyrosine
domains
resulted
two
vertebrate
pseudokinases,
EphA10
EphB6,
co‐evolving
sequences
generate
new
motifs
likely
be
important
for
both
nucleotide
binding
catalysis‐independent
signalling.
Secondly,
conformationally
flexible
Tribbles
have
radiated
complex
vertebrates,
control
fundamental
aspects
cell
signalling
may
targetable
with
covalent
small
molecules.
Finally,
show
species‐level
duplicated
serine
histone
(PSKH)1
sequence
led
appearance
PSKH2,
whose
physiological
role
remains
mysterious.
conclusion,
patterns
discover
selectively
specific
when
they
modelled
alongside
closely
related
kinases,
found
located
functionally
regions
fold.
Interrogation
these
will
useful
future
evaluation
these,
other,
unstudied
human
kinome.
Cell Reports,
Год журнала:
2023,
Номер
42(3), С. 112195 - 112195
Опубликована: Март 1, 2023
Naive
CD4+
T
cells
are
more
resistant
to
age-related
loss
than
naive
CD8+
cells,
suggesting
mechanisms
that
preferentially
protect
during
aging.
Here,
we
show
TRIB2
is
abundant
in
and
counteracts
quiescence
exit
by
suppressing
AKT
activation.
deficiency
increases
activity
accelerates
proliferation
differentiation
response
interleukin-7
(IL-7)
humans
lymphopenia
mice.
transcription
controlled
the
lineage-determining
factors
ThPOK
RUNX3.
Ablation
of
Zbtb7b
(encoding
ThPOK)
Cbfb
(obligatory
RUNT
cofactor)
attenuates
difference
lymphopenia-induced
between
cells.
In
older
adults,
expression
wanes
causing
naivety.
These
findings
assign
a
key
role
regulating
cell
homeostasis
provide
model
explain
lesser
resilience
undergo
changes
with
age.
FEBS Journal,
Год журнала:
2019,
Номер
287(19), С. 4170 - 4182
Опубликована: Окт. 17, 2019
Advances
in
the
understanding
of
Tribbles
family
pseudokinases
(TRIB1,
TRIB2
and
TRIB3)
reveal
these
proteins
as
potentially
valuable
biomarkers
disease
diagnosis,
prognosis,
prediction
clinical
strategy.
In
their
role
signalling
mediators
scaffolding
proteins,
TRIBs
lead
to
changes
protein
stability
activity,
which
impact
on
diverse
cellular
processes
such
proliferation,
differentiation,
cell
cycle
death.
We
review
TRIB
promising
therapeutic
targets,
with
an
emphasis
cancer,
biomarkers,
potential
application
across
pathological
processes.