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PDBsum entry 2psm
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the interleukin-15{middle dot}interleukin-15 receptor {alpha} complex: insights into trans and cis presentation.
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Authors
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S.K.Olsen,
N.Ota,
S.Kishishita,
M.Kukimoto-Niino,
K.Murayama,
H.Uchiyama,
M.Toyama,
T.Terada,
M.Shirouzu,
O.Kanagawa,
S.Yokoyama.
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Ref.
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J Biol Chem, 2007,
282,
37191-37204.
[DOI no: ]
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PubMed id
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Abstract
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Interleukin (IL)-15 is a pleiotropic cytokine that plays a pivotal role in both
innate and adaptive immunity. IL-15 is unique among cytokines due to its
participation in a trans signaling mechanism in which IL-15 receptoralpha
(IL-15Ralpha) from one subset of cells presents IL-15 to neighboring
IL-2Rbeta/gamma(c)-expressing cells. Here we present the crystal structure of
IL-15 in complex with the sushi domain of IL-15Ralpha. The structure reveals
that thealpha receptor-binding epitope of IL-15 adopts a unique conformation,
which, together with amino acid substitutions, permits specific interactions
with IL-15Ralpha that account for the exceptionally high affinity of the
IL-15.IL-15Ralpha complex. Interestingly, analysis of the topology of IL-15 and
IL-15Ralpha at the IL-15.IL-15Ralpha interface suggests that IL-15 should be
capable of participating in a cis signaling mechanism similar to that of the
related cytokine IL-2. Indeed, we present biochemical data demonstrating that
IL-15 is capable of efficiently signaling in cis through IL-15Ralpha and
IL-2Rbeta/gamma(c) expressed on the surface of a single cell. Based on our data
we propose that cis presentation of IL-15 may be important in certain biological
contexts and that flexibility of IL-15Ralpha permits IL-15 and its three
receptor components to be assembled identically at the ligand-receptor interface
whether IL-15 is presented in cis or trans. Finally, we have gained insights
into IL-15.IL-15Ralpha.IL-2Rbeta.gamma(c) quaternary complex assembly through
the use of molecular modeling.
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Figure 3.
FIGURE 3. Comparison of surface electrostatic charge at the
IL-15·IL-15R  and IL-2·IL-2R
interfaces. A,
IL-15·IL-15R and B,
IL-2·IL-2R complexes are shown as
molecular surface representations in an open book view. Selected
residues are labeled. Electrostatic potentials are mapped onto
the molecular surfaces, with negative potential colored red and
positive potential colored blue. Sites 1 and 2 of the
IL-15·IL-15R complex and patches 1
and 2 of IL-2·IL-2R complex are indicated
with a dashed cyan line and labeled. Note the presence of a
negatively charged groove on IL-15 into which the three knobs of
positive potential (Arg-25, Arg-27, and Arg-36) insert. The
electrostatic potentials were calculated, and the figure was
prepared using the program CCP4mg (38).
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Figure 7.
FIGURE 7. Comparison of IL-15 quaternary complex model and
IL-2 quaternary complex. The superimposed structures are shown
as ribbon representations and are colored as in Fig. 6A. Note
that the distinct conformation of the hA-hB loop of IL-15 places
this region of the ligand into the vicinity of the hC-hC'1 loop
of  [c] where unique
interactions can potentially take place. Also note the position
and length of hA of IL-15 and IL-2 quaternary complex interface.
IL-2 residues Leu-12, Glu-15, Leu-18, and Leu-19 from the
N-terminal portion of hA participate in interactions at a
three-way junction between IL-2·IL-2Rβ and [c] that
is suggested to mediate cooperative binding. Due to the shorter
hA of IL-15, it has no homologous residue to Leu-12 of IL-2.
Furthermore, IL-2 residues Glu-15, Leu-18, and Leu-19 have
diverged to Ile-3, Arg-6, and Tyr-7 in IL-15 making it unlikely
that a homologous set of interactions takes place at the
IL-15·IL-2Rβ/ [c] junction.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
37191-37204)
copyright 2007.
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