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Primary and secondary dimer interfaces of the fibroblast growth factor receptor 3 transmembrane domain: characterization via multiscale molecular dynamics simulations.
[achondroplasia]
Receptor
tyrosine
kinases
are
single
-pass
membrane
proteins
that
form
dimers
within
the
membrane
.
The
interactions
of
their
transmembrane
domains
(
TMDs
)
play
a
key
role
in
dimerization
and
signaling
.
Fibroblast
growth
factor
receptor
3
(
FGFR
3
)
is
of
interest
as
a
G
380
R
mutation
in
its
TMD
is
the
underlying
cause
of
~
99
%
of
the
cases
of
achondroplasia
,
the
most
common
form
of
human
dwarfism
.
The
structural
consequences
of
this
mutation
remain
uncertain
:
the
mutation
shifts
the
position
of
the
TMD
relative
to
the
lipid
bilayer
but
does
not
alter
the
association
free
energy
.
We
have
combined
coarse
-grained
and
all-atom
molecular
dynamics
simulations
to
study
the
dimerization
of
wild-
type
,
heterodimer
,
and
mutant
FGFR
3
TMDs
.
The
simulations
reveal
that
the
helices
pack
together
in
the
dimer
to
form
a
flexible
interface
.
The
primary
packing
mode
is
mediated
by
a
Gx
3
G
motif
.
There
is
also
a
secondary
dimer
interface
that
is
more
highly
populated
in
heterodimer
and
mutant
configurations
that
may
feature
in
the
molecular
mechanism
of
pathology
.
Both
coarse
-grained
and
atomistic
simulations
reveal
a
significant
shift
of
the
G
380
R
mutant
dimer
TMD
relative
to
the
bilayer
to
allow
interactions
of
the
arginine
side
chain
with
lipid
headgroup
phosphates
.
Diseases
Validation
Diseases presenting
"common form"
symptom
achondroplasia
alexander disease
benign recurrent intrahepatic cholestasis
cadasil
child syndrome
classical phenylketonuria
cutaneous mastocytosis
erythropoietic protoporphyria
familial mediterranean fever
hereditary cerebral hemorrhage with amyloidosis
hodgkin lymphoma, classical
holt-oram syndrome
homocystinuria without methylmalonic aciduria
oral submucous fibrosis
pendred syndrome
primary hyperoxaluria type 1
severe combined immunodeficiency
thoracic outlet syndrome
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