Journal of Molecular Biology,
Journal Year:
2023,
Volume and Issue:
436(3), P. 168332 - 168332
Published: Oct. 29, 2023
A
dozen
bHLH-PAS
transcription
factors
have
evolved
since
the
dawn
of
animal
kingdom;
nine
them
mutual
orthologs
between
arthropods
and
vertebrates.
These
proteins
are
master
regulators
in
a
range
developmental
processes
from
organogenesis,
nervous
system
formation
functioning,
to
cell
fate
decisions
defining
identity
limbs
or
photoreceptors
for
color
vision.
Among
functionally
best
conserved
acting
circadian
clock.
On
other
side
spectrum
fundamental
physiological
mechanisms
such
as
those
underlying
xenobiotic
detoxification,
oxygen
homeostasis,
metabolic
adaptation
hypoxia,
infection
tumor
progression.
Predictably,
malfunctioning
leads
pathologies.
Performance
individual
is
modulated
at
multiple
levels
including
dimerization
protein–protein
interactions,
proteasomal
degradation,
by
binding
low-molecular
weight
ligands.
Despite
vast
evolutionary
gap
dividing
vertebrates,
differences
their
anatomy,
many
functions
orthologous
remarkably
similar,
molecular
level.
Our
phylogenetic
analysis
shows
that
one
protein
type
has
been
lost
during
vertebrate
evolution.
This
unique
function
receptor
sesquiterpenoid
juvenile
hormones
insects
crustaceans.
Although
some
regulated
small
molecules,
hormone
presents
an
unprecedented
case,
all
non-peptide
activate
members
nuclear
family.
The
purpose
this
review
compare
highlight
parallels
functioning
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Jan. 4, 2024
Abstract
Transcription
factors
of
the
bHLH-PAS
family
play
vital
roles
in
animal
development,
physiology,
and
disease.
Two
members
require
binding
low-molecular
weight
ligands
for
their
activity:
vertebrate
aryl
hydrocarbon
receptor
(AHR)
insect
juvenile
hormone
(JHR).
In
fly
Drosophila
melanogaster
,
paralogous
proteins
GCE
MET
constitute
ligand-binding
component
JHR
complexes.
Whilst
GCE/MET
AHR
are
phylogenetically
heterologous,
mode
action
is
similar.
targeted
by
several
synthetic
agonists
that
serve
as
insecticides
disrupting
endocrine
system.
an
important
regulator
human
homeostasis
it
responds
to
environmental
pollutants
disruptors.
Whether
signaling
affected
compounds
can
activate
has
not
been
reported.
To
address
this
question,
we
screened
a
chemical
library
50,000
identify
93
novel
reporter
system
based
on
cells.
Of
these
compounds,
26%
modulated
analogous
assay
cell
line,
indicating
significant
overlap
agonist
repertoires
two
receptors.
explore
structural
features
agonist-dependent
activation
AHR,
compared
cavities
interactions
with
selective
common
GCE.
Molecular
dynamics
modeling
revealed
ligand-specific
well
conserved
side
chains
within
respective
cavities.
Significance
predicted
was
supported
through
site-directed
mutagenesis.
The
results
have
indicated
might
interfere
Current Opinion in Insect Science,
Journal Year:
2024,
Volume and Issue:
65, P. 101234 - 101234
Published: July 20, 2024
Juvenile
hormone
(JH)
signaling
is
realized
at
the
gene
regulatory
level
by
receptors
of
bHLH-PAS
transcription
factor
family.
The
sesquiterpenoid
hormones
and
their
synthetic
mimics
are
agonist
ligands
a
unique
JH
receptor
(JHR)
protein,
methoprene-tolerant
(MET).
Upon
binding
an
to
its
PAS-B
cavity,
MET
dissociates
from
cytoplasmic
chaperone
complex
including
HSP83
concomitantly
switches
partner
taiman,
forming
nuclear,
transcriptionally
active
JHR
heterodimer.
This
course
events
resembles
vertebrate
aryl
hydrocarbon
(AHR),
activated
plethora
endogenous
compounds.
Like
in
AHR,
pliable
cavity
adjusts
diverse
binds
them
through
similar
mechanisms.
Despite
recent
progress,
we
only
begin
discern
agonist-induced
conformational
shifts
within
domain,
with
ultimate
goal
understanding
how
these
localized
changes
stimulate
assembly
and,
thus,
fully
grasp
mechanism
signaling.
