Nature Communications,
Год журнала:
2020,
Номер
11(1)
Опубликована: Июнь 23, 2020
Abstract
SAMHD1
regulates
cellular
2′-deoxynucleoside-5′-triphosphate
(dNTP)
homeostasis
by
catalysing
the
hydrolysis
of
dNTPs
into
2′-deoxynucleosides
and
triphosphate.
In
CD4
+
myeloid
lineage
resting
T-cells,
blocks
HIV-1
other
viral
infections
depletion
dNTP
pool
to
a
level
that
cannot
support
replication.
mutations
are
associated
with
autoimmune
disease
Aicardi–Goutières
syndrome
hypermutated
cancers.
Furthermore,
sensitises
cancer
cells
nucleoside-analogue
anti-cancer
therapies
is
linked
DNA
repair
suppression
interferon
response
cytosolic
nucleic
acids.
Nevertheless,
despite
its
requirement
in
these
processes,
fundamental
mechanism
SAMHD1-catalysed
remained
unknown.
Here,
we
present
structural
enzymological
data
showing
utilises
an
active
site,
bi-metallic
iron-magnesium
centre
positions
hydroxide
nucleophile
in-line
P
α
-O
5′
bond
catalyse
phosphoester
hydrolysis.
This
precise
molecular
for
catalysis,
reveals
how
down-regulates
modulates
efficacy
nucleoside-based
anti-viral
therapies.
Biochemistry,
Год журнала:
2016,
Номер
55(44), С. 6087 - 6099
Опубликована: Окт. 24, 2016
Sterile
alpha
motif
and
HD
domain
protein
1
(SAMHD1)
is
a
unique
enzyme
that
plays
important
roles
in
nucleic
acid
metabolism,
viral
restriction,
the
pathogenesis
of
autoimmune
diseases
cancer.
Although
much
attention
has
been
focused
on
its
dNTP
triphosphohydrolase
activity
restriction
disease,
SAMHD1
also
binds
to
single-stranded
RNA
DNA.
Here
we
utilize
UV
cross-linking
method
using
5-bromodeoxyuridine-substituted
oligonucleotides
coupled
with
high-resolution
mass
spectrometry
identify
binding
site
for
acids
(ssNAs)
SAMHD1.
Mapping
cross-linked
amino
surface
existing
crystal
structures
demonstrated
ssNA
lies
largely
along
dimer-dimer
interface,
sterically
blocking
formation
homotetramer
required
dNTPase
activity.
Surprisingly,
disordered
C-terminus
(residues
583-626)
was
implicated
binding.
An
interaction
between
this
region
confirmed
studies
purified
583-626
peptide.
Despite
recent
report
possesses
polyribonucleotide
phosphorylase
activity,
did
not
detect
any
such
presence
inorganic
phosphate,
indicating
unrelated
proposed
These
data
suggest
an
antagonistic
regulatory
mechanism
which
mutually
exclusive
oligomeric
state
requirements
hydrolase
modulate
these
two
functions
within
cell.
Antioxidants and Redox Signaling,
Год журнала:
2017,
Номер
27(16), С. 1317 - 1331
Опубликована: Фев. 24, 2017
Proliferative
signaling
involves
reversible
posttranslational
oxidation
of
proteins.
However,
relatively
few
molecular
targets
these
modifications
have
been
identified.
We
investigate
the
role
protein
in
regulation
SAMHD1
catalysis.Here
we
report
that
is
a
major
target
for
redox
nucleotide
metabolism
and
cell
cycle
control.
triphosphate
hydrolase,
whose
function
deoxynucleotide
pools.
demonstrate
state
regulates
its
catalytic
activity.
identified
three
cysteine
residues
constitute
an
intrachain
disulfide
bond
"redox
switch"
reversibly
inhibits
tetramerization
catalysis.
show
proliferative
signals
lead
to
cells
oxidized
localized
outside
nucleus.
Innovation
Conclusions:
activity
regulated
by
oxidation.
These
data
identify
previously
unknown
mechanism
SAMHD1.
Antioxid.
Redox
Signal.
27,
1317-1331.
Cell Reports,
Год журнала:
2020,
Номер
30(12), С. 3972 - 3980.e5
Опубликована: Март 1, 2020
Macrophages
exist
predominantly
in
two
distinct
states,
G0
and
a
G1-like
state
that
is
accompanied
by
phosphorylation
of
SAMHD1
at
T592.
Here,
we
demonstrate
Toll-like
receptor
4
(TLR4)
activation
can
potently
induce
arrest
antiretroviral
activity
an
interferon
(IFN)-independent
pathway.
This
pathway
requires
TLR4
engagement
with
TRIF,
but
not
involvement
TBK1
or
IRF3.
Exclusive
Myd88
activators
are
unable
to
trigger
dephosphorylation,
demonstrating
this
also
Myd88/nuclear
factor
κB
(NF-κB)
independent.
The
p21
upregulation
CDK1
depletion,
consistent
the
observed
dephosphorylation
Furthermore,
show
knockdown
TLR4-activated
blocks
HIV-1
infection
macrophages
specifically
via
SAMHD1.
Together,
these
data
mobilize
intrinsic
cell
anti-viral
activating
prior
IFN
secretion,
thereby
highlighting
importance
cell-cycle
regulation
as
response
pathogen-associated
danger
signals
macrophages.
Nature Communications,
Год журнала:
2020,
Номер
11(1)
Опубликована: Июнь 23, 2020
Abstract
SAMHD1
regulates
cellular
2′-deoxynucleoside-5′-triphosphate
(dNTP)
homeostasis
by
catalysing
the
hydrolysis
of
dNTPs
into
2′-deoxynucleosides
and
triphosphate.
In
CD4
+
myeloid
lineage
resting
T-cells,
blocks
HIV-1
other
viral
infections
depletion
dNTP
pool
to
a
level
that
cannot
support
replication.
mutations
are
associated
with
autoimmune
disease
Aicardi–Goutières
syndrome
hypermutated
cancers.
Furthermore,
sensitises
cancer
cells
nucleoside-analogue
anti-cancer
therapies
is
linked
DNA
repair
suppression
interferon
response
cytosolic
nucleic
acids.
Nevertheless,
despite
its
requirement
in
these
processes,
fundamental
mechanism
SAMHD1-catalysed
remained
unknown.
Here,
we
present
structural
enzymological
data
showing
utilises
an
active
site,
bi-metallic
iron-magnesium
centre
positions
hydroxide
nucleophile
in-line
P
α
-O
5′
bond
catalyse
phosphoester
hydrolysis.
This
precise
molecular
for
catalysis,
reveals
how
down-regulates
modulates
efficacy
nucleoside-based
anti-viral
therapies.