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Structural features of recombinant MMADHC isoforms and their interactions with MMACHC, proteins of mammalian vitamin B12 metabolism.
[homocystinuria without methylmalonic aciduria]
The
genes
MMACHC
and
MMADHC
encode
critical
proteins
involved
in
the
intracellular
metabolism
of
cobalamin
.
Two
clinical
features
,
homocystinuria
and
methylmalonic
aciduria
,
define
inborn
errors
of
these
genes
.
Based
on
disease
phenotypes
,
MMADHC
acts
at
a
branch
point
for
cobalamin
delivery
,
apparently
exerting
its
function
through
interaction
with
MMACHC
that
demonstrates
dealkylase
and
decyanase
activities
.
Here
we
present
biophysical
analyses
of
MMADHC
to
identify
structural
features
and
to
further
characterize
its
interaction
with
MMACHC
.
Two
recombinant
tag-less
isoforms
of
MMADHC
(
MMADHCΔ
1
-
12
and
MMADHCΔ
1
-
61
)
were
expressed
and
purified
.
Full
length
MMACHC
and
full
length
MMADHC
were
detected
in
whole
cell
lysates
of
human
cells
;
by
Western
blotting
,
their
molecular
masses
corresponded
to
purified
recombinant
proteins
.
By
clear-native
PAGE
and
by
dynamic
light
scattering
,
recombinant
MMADHCs
were
stable
and
monodisperse
.
Both
species
were
monomeric
,
adopting
extended
conformations
in
solution
.
Circular
dichroism
and
secondary
structure
predictions
correlated
with
significant
regions
of
disorder
within
the
N-
terminal
domain
of
MMADHC
.
We
found
no
evidence
that
MMADHC
binds
cobalamin
.
Phage
panning
against
MMADHC
predicted
four
binding
regions
on
MMACHC
,
two
of
which
overlap
with
predicted
sites
on
MMACHC
at
which
it
may
self-associate
.
Specific
,
concentration-dependent
responses
were
observed
for
MMACHC
binding
to
itself
and
to
both
MMADHC
constructs
.
As
estimated
in
the
sub-micromolar
range
,
the
binding
of
MMACHC
to
itself
was
weaker
compared
to
its
interaction
with
either
of
the
MMADHC
isoforms
.
We
propose
that
the
function
of
MMADHC
is
exerted
through
its
structured
C-
terminal
domain
via
interactions
with
MMACHC
.
Diseases
Validation
Diseases presenting
"homocystinuria"
symptom
adrenomyeloneuropathy
cohen syndrome
homocystinuria without methylmalonic aciduria
primary hyperoxaluria type 1
pyruvate dehydrogenase deficiency
This symptom has already been validated