bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2022,
Номер
unknown
Опубликована: Сен. 3, 2022
ABSTRACT
Netrins
can
dictate
attractive
and
repulsive
responses
during
axon
growth
cell
migration,
where
presence
of
the
receptor
UNC-5
on
target
cells
results
in
Netrin-mediated
repulsion.
Molecular
details
Netrin–UNC-5
interactions
how
they
signal
remain
elusive.
Here,
we
show
that
nematode
is
a
heparin-binding
protein,
UNC-5–heparin
affinity
be
modulated
using
directed
evolution
or
via
rational
design
our
novel
structure
with
heparin
fragment.
Furthermore,
UNC-6/Netrin
form
large,
stable
rigid
oligomeric
complex
heparin,
which
incorporate
UNC-40/DCC
receptor,
demonstrating
binary
ternary
ectodomain
complexes
at
preparative
scale.
C.
elegans
deficient
fail
to
establish
proper
gonad
morphology
due
abrogated
distal
tip
relies
signaling
response
UNC-6.
Our
findings
Netrin
mediated
through
glycosaminoglycan-regulated
large
macromolecular
complexes.
Developmental Dynamics,
Год журнала:
2022,
Номер
252(1), С. 27 - 60
Опубликована: Июнь 21, 2022
One
of
the
fundamental
properties
a
neuronal
circuit
is
map
its
connections.
The
cellular
and
developmental
processes
that
allow
for
growth
axons
dendrites,
selection
synaptic
targets,
formation
functional
synapses
use
surface
receptors
their
interactions
with
other
receptors,
secreted
ligands,
matrix
molecules.
Spatiotemporal
regulation
expression
these
cues
allows
specificity
in
pathways
wire
stereotyped
circuits.
families
molecules
controlling
axon
guidance
synapse
are
generally
conserved
across
animals,
some
important
exceptions,
which
have
consequences
connectivity.
Here,
we
summarize
distribution
such
multiple
taxa,
focus
on
model
organisms,
evolutionary
led
to
multitude
molecules,
diversification
or
loss
receptors.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Авг. 17, 2023
Abstract
Synaptic
adhesion
molecules
(SAMs)
shape
the
structural
and
functional
properties
of
synapses
thereby
control
information
processing
power
neural
circuits.
SAMs
are
broadly
expressed
in
brain,
suggesting
that
they
may
instruct
synapse
formation
specification
via
a
combinatorial
logic.
Here,
we
generate
sextuple
conditional
knockout
mice
targeting
all
members
two
major
families
presynaptic
SAMs,
Neurexins
leukocyte
common
antigen-related-type
receptor
phospho-tyrosine
phosphatases
(LAR-PTPRs),
which
together
account
for
majority
known
trans-synaptic
complexes.
Using
formed
by
cerebellar
Purkinje
cells
onto
deep
nuclei
as
model
system,
confirm
LAR-PTPRs
themselves
not
essential
assembly.
The
deletion
both
neurexins
LAR-PTPRs,
however,
decreases
Purkinje-cell
on
nuclei,
output
pathway
Consistent
with
this
finding,
combined
but
separate
deletions
impair
motor
behaviors.
Thus,
required
assembly
circuit.
Current Biology,
Год журнала:
2024,
Номер
34(5), С. 980 - 996.e6
Опубликована: Фев. 12, 2024
Tissue-intrinsic
error
correction
enables
epithelial
cells
to
detect
abnormal
neighboring
and
facilitate
their
removal
from
the
tissue.
One
of
these
pathways,
"interface
surveillance,"
is
triggered
by
with
aberrant
developmental
cell-fate-patterning
pathways.
It
remains
unknown
which
molecular
mechanisms
provide
ability
compare
fate
between
cells.
We
demonstrate
that
Drosophila
imaginal
discs
express
an
array
cell
surface
molecules
previously
implicated
in
neuronal
axon
guidance
processes.
They
include
members
Robo,
Teneurin,
Ephrin,
Toll-like,
or
atypical
cadherin
families.
Importantly,
a
mismatch
expression
levels
adjacent
sufficient
induce
interface
surveillance,
indicating
differences
cells,
rather
than
absolute
levels,
are
crucial.
Specifically,
Robo2
Robo3,
but
not
Robo1,
induces
enrichment
actin,
myosin
II,
Ena/Vasp,
as
well
activation
JNK
apoptosis
at
clonal
interfaces.
Moreover,
can
surveillance
independently
its
cytosolic
domain
without
need
for
Robo-ligand
Slit.
The
other
molecules,
such
Teneurins
Ephrin
receptor
regulated
fate-patterning
pathways
intrinsic
extrinsic
wing
disc,
oncogenic
RasV12.
Combined,
we
respond
code
patterns
mediated
specific
transmembrane
proteins
reveal
novel
function
recognition
during
development
homeostasis
tissues.
ACS Chemical Neuroscience,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 2, 2025
The
nectin
family
of
cell
adhesion
molecules
(CAMs)
comprising
nectins
and
nectin-like
has
emerged
as
a
key
regulator
various
pivotal
neural
processes,
including
neuronal
development,
migration,
synapse
formation,
plasticity.
Nectins
engage
in
homophilic
heterophilic
interactions
to
mediate
cell-cell
adhesion,
contributing
the
establishment
maintenance
circuits.
Their
extracellular
domains
facilitate
trans-synaptic
interactions,
while
intracellular
participate
signaling
cascades
influencing
cytoskeletal
dynamics
synaptic
function.
exhibition
distinct
localization
patterns
neurons,
astrocytes,
blood-brain
barrier
underscores
their
diverse
roles
brain.
dysregulation
been
implicated
several
neurological
disorders,
such
neurodevelopmental
depression,
schizophrenia,
Alzheimer's
disease.
This
review
examines
structural
functional
characteristics
distribution
molecular
mechanisms
governing
connectivity
cognition.
It
further
discusses
experimental
studies
unraveling
nectin-mediated
pathophysiology
potential
therapeutic
interventions
targeting
nectin-related
pathways.
Collectively,
this
comprehensive
analysis
highlights
significance
brain
function,
paving
way
for
future
research
directions
clinical
implications.
Current Opinion in Neurobiology,
Год журнала:
2025,
Номер
92, С. 102999 - 102999
Опубликована: Март 20, 2025
Guidance
of
nascent
axons
to
their
targets
is
mediated
by
attractive
and
repulsive
cues
that
activate
receptors
on
the
axonal
growth
cone.
The
number
ligand-receptor
interactions
implicated
in
axon
pathfinding
still
expanding,
large-scale
cell-surface
extracellular
protein
interactome
studies
have
revealed
extensive
crosstalk
between
signaling
axes
once
thought
act
independently.
This
raises
question
how
apparent
promiscuity
molecular
compatible
with
specific
outcomes
effects
cone
steering.
Structural
provided
insights
into
modularity
binding
shown
capacity
engage
multiple
ligands.
Here,
we
review
recent
findings
about
complexity
interaction
networks
for
guidance,
structures
complexes
reveal
mechanisms
may
specify
output.
PLoS Computational Biology,
Год журнала:
2025,
Номер
21(4), С. e1012813 - e1012813
Опубликована: Апрель 14, 2025
The
Immunoglobulin
fold
(Ig-fold)
is
found
in
proteins
from
all
domains
of
life
and
represents
the
most
populous
human
genome,
with
current
estimates
ranging
2
to
3%
protein
coding
regions.
That
proportion
much
higher
surfaceome
where
Ig
Ig-like
orchestrate
cell-cell
recognition,
adhesion
signaling.
ability
Ig-domains
reliably
self-assemble
through
highly
specific
interfaces
a
remarkable
property
these
domains,
making
them
key
elements
molecular
interaction
systems:
immune
system,
nervous
vascular
system
muscular
system.
We
define
universal
residue
numbering
scheme,
common
sharing
Ig-fold
order
study
wide
spectrum
Ig-domain
variants
constituting
Ig-proteome
Ig-Ig
interactomes
at
heart
systems
.
“IgStrand
scheme”
enables
identification
structural
proteomes
between
any
species,
comparative
structural,
functional,
evolutionary
analyses.
review
how
are
classified
today
as
topological
highlight
“Ig-fold
irreducible
signature”
shared
by
them.
IgStrand
scheme
lays
foundation
for
systematic
annotation
detecting
accurately
labeling
Ig-,
Ig-extended
proteins,
which
poorly
annotated
databases
opens
door
accurate
machine
learning.
Importantly,
it
sheds
light
on
robust
folding
algorithm
used
nature
form
beta
sandwich
supersecondary
structures.
powers
an
implemented
interactive
analysis
software
iCn3D
systematically
recognize
Ig-domains,
annotate
perform
detailed
analyses
comparing
domain
sequence,
topology
structure,
regardless
their
diverse
topologies
or
origin.
provides
detection
mechanism
that
reveals
unsuspected
homologies
among
structures
beyond
currently
identified
Ig-
variants.
Indeed,
multiple
folds
independently
contain
signature,
particular
jelly-rolls.
Examples
harbor
“Ig-extended”
architecture
given.
Applications
engineering
around
Ig-architecture
straightforward
based
numbering.
Netrins
dictate
attractive
and
repulsive
responses
during
axon
growth
cell
migration,
where
the
presence
of
receptor
Uncoordinated-5
(UNC-5)
on
target
cells
results
in
repulsion.
Here,
we
showed
that
UNC-5
is
a
heparin-binding
protein,
determined
its
structure
bound
to
heparin
fragment,
could
modulate
UNC-5–heparin
affinity
using
directed
evolution
platform
or
structure-based
rational
design.
We
demonstrated
UNC-6/netrin
form
large,
stable,
rigid
complex
heparin,
exclude
UNC-40/DCC
from
binding
large
extent.
Caenorhabditis
elegans
with
heparin-binding–deficient
fail
establish
proper
gonad
morphology
due
abrogated
which
relies
signaling
response
UNC-6.
Combining
mutations
targeting
contacts
complete
migration
guidance
defects.
Our
findings
netrin
be
mediated
through
glycosaminoglycan-regulated
macromolecular
complex.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 11, 2024
ABSTRACT
The
Immunoglobulin
fold
(Ig-fold)
is
found
in
proteins
from
all
domains
of
life
and
represents
the
most
populous
human
genome,
with
current
estimates
ranging
2
to
3%
protein
coding
regions.
That
proportion
much
higher
surfaceome
where
Ig
Ig-like
orchestrate
cell-cell
recognition,
adhesion
signaling.
ability
Ig-domains
reliably
self-assemble
through
highly
specific
interfaces
a
remarkable
property
these
domains,
making
them
key
elements
molecular
interaction
systems:
immune
system,
nervous
vascular
system
muscular
system.
We
define
universal
residue
numbering
scheme,
common
sharing
Ig-fold
order
study
wide
spectrum
Ig-domain
variants
constituting
Ig-proteome
Ig-Ig
interactomes
at
heart
systems
.
“IgStrand
scheme”
enables
identification
structural
proteomes
between
any
species,
comparative
structural,
functional,
evolutionary
analyses.
review
how
are
classified
today
as
topological
highlight
“Ig-fold
irreducible
signature”
shared
by
them.
IgStrand
scheme
lays
foundation
for
systematic
annotation
detecting
accurately
labeling
Ig-,
Ig-extended
proteins,
which
poorly
annotated
databases
opens
door
accurate
machine
learning.
Importantly,
it
sheds
light
on
robust
folding
algorithm
used
nature
form
beta
sandwich
supersecondary
structures.
powers
an
implemented
interactive
analysis
software
iCn3D
systematically
recognize
Ig-domains,
annotate
perform
detailed
analyses
comparing
domain
sequence,
topology
structure,
regardless
their
diverse
topologies
or
origin.
provides
detection
mechanism
that
reveals
unsuspected
homologies
among
structures
beyond
currently
identified
Ig-
variants.
Indeed,
multiple
folds
independently
contain
signature,
particular
jelly-rolls.
Examples
harbor
“Ig-extended”
architecture
given.
Applications
engineering
around
Ig-architecture
straightforward
based
numbering.
AUTHOR
SUMMARY
conserved
has
diversified
extensively
throughout
evolution
provide
significant
number
types
variable
forms.
Primarily
known
its
role
vertebrate
presence
structure
antibodies,
myriad
involved
biological/structural
functions
within
immune,
nervous,
vascular,
systems,
they
mediate
neural
development,
cell
Structurally,
consists
70-110
amino
acids
two
sheets
stabilized
hydrogen
bonds
facing
each
other
configuration.
This
stability
tremendous
adaptability,
fundamental
building
block
many
families
across
bacteria
vertebrates.
abundant
accounting
least
2-3%
protein-coding
regions,
underestimate
no
reliable
method
exists
date
can
identify
precision.
To
better
importantly
interactions
behind
biological
functions,
was
developed.
It
down
level
interactions,
allowing
deconstruction
variant
tertiary
quaternary
will
assist
rational
design
scratch
Ig-based
therapeutics
single-domain
antibodies
cellular
therapies
against
antigen
interest.