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Class
I
phosphoinositide
3-­-kinases
in
immunity…

least
in
certain
cases
Ras-­-family
proteins
might
play
an
active
role
in
recruiting
to

membranes
catalytic
class
IA
(15)
and
class
IB
subunits
(10).

Figure
2.
Structure
of
the
catalytic
and
regulatory
subunits
of
mammalian
PI3K
classes
and

subclasses.
Size
in
kDa
is
indicated
in
the
name
of
class
I
PI3K,
all
proteins
are
represented
at
the

same
approximate
scale.
PI3K
catalytic
subunits
contain
a
common
core
of
one
C2
domain,
one

helical
domain,
and
one
catalytic
kinase
domain.
Class
IA
and
IB
catalytic
subunits
(a,
ß,
d,
and
?)

are
the
product
of
single
genes
;
they
have
two
domains
N-­-terminal
to
the
core,
namely
an
adaptor

binding
domain
(ABD)
that
binds
to
regulatory
subunit,
and
one
Ras-­-binding
domain
where
binding

of
Ras
family
proteins
activate
the
kinase
activity.
A;
B)
Class
IA
catalytic
subunits
(a,
ß,
and
d)

associate
with
any
class
IA
regulatory
subunits
encoded
by
three
different
genes.
Pik3r1
can

produce
three
different
proteins
(p85a,
p55a
and
p50a)
sharing
one
Pro-­-rich
region,
plus
one
N-­-
terminal
and
one
C-­-terminal
SH2
domains
separated
by
and
inter-­-SH2
domain
(iSH2)
that
binds
the

ABD
domain
in
the
catalytic
a,
ß,
and
d
subunits.
The
p85a
subunit
has
one
N-­-terminal
SH3,
one

Proline-­-rich,
and
one
BH
(BCR
homology)
domain;
the
p85ß
subunit
coded
by
the
Pik3r2
gene
is

similar
to
p85a
subunit
but
has
an
additional
c-­-terminal
Pro-­-rich
region.
The
p55?
subunit
encoded

by
Pik3r3
and
p55a
have
similar
structures.
C)
Class
IB
catalytic
subunits
(p110?)
bind
to
p87
or

p101
class
IB
regulatory
subunits
endowed
with
domains
able
of
associating
to
the
Ga
and
Gß

subunits
of
heterotrimeric
Guanine
nucleotide-­-binding
proteins
(G
proteins)
that
initiate
signals

delivered
by
G-­-protein
coupled
receptors
(GPCR).
D)
Class
II
PI3Ks
do
not
have
regulatory
subunits,

and
seem
to
be
constitutively
bound
to
intracellular
membranes.
They
have
a
role
in
different
cell

functions
including
cell
migration,
exocytosis,
and
apoptosis,
but
the
precise
mechanisms
involved

are
not
clear.
The
Class
III
catalytic
subunit
Vps34
(Vacuolar
protein
sorting
34,
also
termed

PIK3C3)
is
part
of
a
heterodimer
with
the
myristoylated
protein
Vps15,
that
is
located
in
the
cell

membranes
and
form
larger
multi-­-protein
complexes
depending
on
the
particular
vesicle
traffic

process
considered
(autophagy,
phagocytosis,
endosome
traffic).
Vps15
has
a
kinase
domain

probably
inactive,
HEAT
domains
containing
anti-­-parallel
a-­-helices
involved
in
protein-­-protein

interactions;
and
WD
repeats
that
serve
as
scaffolds
for
interaction
with
other
proteins.

Regulatory
subunits
inhibit
the
catalytic
activity
of
the
p110
subunits
but

also
prevent
their
degradation.
Activation
of
PI3K
begins
upon
recruitment
of
the

enzyme
complex
through
regulatory
subunits
to
the
inner
side
of
membrane

bilayers
where
their
substrate
is
located,
and
where
interaction
with
the

negatively
charged
surface
through
positively
charged
aminoacid
residues
further

stabilizes
its
location.
This
is
followed
by
interaction
with
and
activation
of
the

95