Cytokines: Interleukins
129
The basic structural characteristics of
HR are two extracellular domains of ap-
proximately 100
amino
acids, the
one
closest to the cell membrane containing
a WSXWS motif and the outer N-terminal
domain containing a number of conserved
cysteine residues (Fig. 3). As new mem-
be
rso
ftheHRfam
i
lywe
reiden
t
i±ed
,i
t
became clear that either (1) these two do-
mains could be duplicated or (2) unrelated
domains that were immunoglobulin-like
or ±bronectin-like could be added to extend
the extracellular portion of the receptor. In
the case of the GH receptor, which has the
simplest two domain structure (Fig. 3), X-
crystallography has recently shown that
each of the 100 amino acid stretches con-
sists of seven ß-strands that are folded to
form a sandwich of two antiparallel sheets.
However, only
the
N-terminal
domain
makes contact with the GH molecule. In
fact, the GH molecule is able to bind to
two GH receptors, thus effecting their
dimerization, a process that is likely to
be required for signal transduction via the
C-terminal intracellular domains.
The G-CSF receptor probably functions
in a similar manner. However, many of the
interleukin receptors are more complex in
that they are composed of more than one
component (subunit). The IL-2 receptor,
for example, has three subunits, the ±rst
(IL-2R
α
) being a glycoprotein unrelated
to the HR family and the second (IL-
2Rß) and third (IL-2R
γ
)be
ingHRfam
i
ly
members. All three subunits can bind IL-
2 with low af±nity, the complexes of
α
-
and ß- and ß- and
γ
-subunits bind IL-2
with intermediate af±nity, but only the
complex of
α
-, ß-, and
γ
-subunits can form
a high-af±nity receptor for IL-2, leading to
signal transduction and internalization of
the ligand–receptor complex (IL-2R
γ
has
been shown to be a subunit of IL-4, IL-7,
IL-13, IL-15, and IL-21 receptors).
In the
case of
IL-3, IL-5,
and GM-
CSF,
a
different
receptor
system
has
evolved whereby ligand binding to a ligand-
speci±c receptor subunit (
α
-chain) induces
the association of this complex with a
nonspeci±c receptor subunit (ß-chain) that
enables signal transduction to take place.
Both
α
-
and
ß-
chains
are
members
of the HR family (Fig. 3). The
α
-chains
have
only
small
cytoplasmic
domains,
insuf±cient for signaling, and therefore the
presence of the ß-chain, which does have
a large cytoplasmic domain, is required
for
signal
transduction.
This
receptor
system explains why IL-3, IL-5, and GM-
CSF share many biological activities since
where cells express all three ligand-speci±c
α
-chains, signaling can only take place
by interaction with the single common,
nonspeci±c, ß-chain yielding the same
cellular response.
A similar receptor system exists for
IL-6 and IL-11 and the cytokines LIF,
CNTF, and OSM. Here the nonspeci±c ß-
chain has been characterized as a 130-kDa
transmembrane glycoprotein (gp130) that
resembles the G-CSF receptor in overall
structure (Fig. 3). Only in the presence
of gp130, which itself cannot bind IL-6,
can a high-af±nity receptor complex be
formed by interaction of the IL-6 binding
α
-chain and signal transduction ensues.
gp130 is also the ß-chain for IL-11, LIF,
CNTF and OSM (gp130 can weakly bind
OSM). The IL-6R
α
chain may be cleaved
from the cell membrane to form a soluble
receptor for IL-6 (sIL-6R
α
), and this can
also interact with IL-6 and gp130 to trigger
signal transduction. Interestingly, IL-12
has two components, a p40 subunit that
is
homologous
to
sIL-6R
α
and
a
p35
subunit that resembles a typical helical
cytokine. In effect, it is an interleukin that
carries its own speci±c
α
-chain around
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