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Contents |
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98 a.a.
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198 a.a.
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286 a.a.
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* Residue conservation analysis
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PDB id:
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Cytokine/cytokine receptor
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Title:
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Crystal structure of the il13-il4r-il13ra ternary complex
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Structure:
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Interleukin 13. Chain: a. Engineered: yes. Interleukin-4 receptor alpha chain. Chain: b. Fragment: extracellular domain, residues 27-227. Synonym: il-4r-alpha, cd124 antigen, soluble interleukin-4 receptor alpha chain. Engineered: yes.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: il13. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: il4r, 582j2.1, il4ra. Gene: il13ra1, il13r, il13ra.
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Resolution:
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3.00Å
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R-factor:
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0.256
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R-free:
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0.312
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Authors:
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K.C.Garcia
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Key ref:
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S.L.LaPorte
et al.
(2008).
Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system.
Cell,
132,
259-272.
PubMed id:
DOI:
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Date:
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18-Dec-07
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Release date:
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05-Feb-08
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PROCHECK
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Headers
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References
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P35225
(IL13_HUMAN) -
Interleukin-13 from Homo sapiens
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Seq:
Struc:
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146 a.a.
98 a.a.
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DOI no:
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Cell
132:259-272
(2008)
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PubMed id:
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Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system.
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S.L.LaPorte,
Z.S.Juo,
J.Vaclavikova,
L.A.Colf,
X.Qi,
N.M.Heller,
A.D.Keegan,
K.C.Garcia.
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ABSTRACT
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Interleukin-4 and Interleukin-13 are cytokines critical to the development of T
cell-mediated humoral immune responses, which are associated with allergy and
asthma, and exert their actions through three different combinations of shared
receptors. Here we present the crystal structures of the complete set of type I
(IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4, IL-4R
alpha/IL-13R alpha1/IL-13) ternary signaling complexes. The type I complex
reveals a structural basis for gamma(c)'s ability to recognize six different
gamma(c)-cytokines. The two type II complexes utilize an unusual top-mounted
Ig-like domain on IL-13R alpha1 for a novel mode of cytokine engagement that
contributes to a reversal in the IL-4 versus IL-13 ternary complex assembly
sequences, which are mediated through substantially different recognition
chemistries. We also show that the type II receptor heterodimer signals with
different potencies in response to IL-4 versus IL-13 and suggest that the
extracellular cytokine-receptor interactions are modulating intracellular
membrane-proximal signaling events.
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Selected figure(s)
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Figure 1.
Figure 1. Structures of the Type I IL-4, Type II IL-4, and
Type II IL-13 Ternary Complexes
(A) The type I complex with
IL-4Rα (blue), IL-4 (red), and γ[c] (gold).
(B) The type
II IL-4 complex with IL-4Rα (blue), IL-4 (red), and IL-13Rα1
(green).
(C) The type II IL-13 complex with IL-4Rα (blue),
IL-13 (yellow-orange), and IL-13Rα1 (green).
The complexes
are shown from the side with a cartoon of a membrane underneath
(left), and as viewed from the “top” (right). Glycan
moieties on Asn residues are shown in ball-and-stick
representation. All figures were generated with PyMol (DeLano,
2002).
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Figure 2.
Figure 2. Structural Similarity between IL-2Rα and IL-13Rα1
Cytokine Engagement
(A) The quaternary complex of IL-2
(pink), IL-2Rα (cyan), IL-2Rβ (blue), and γ[c] (gold).
IL-2Rα is bound to the top surface of IL-2.
(B) Ternary
complex of IL-13 (yellow-orange), IL-4Rα (blue), and IL-13Rα1
(green).
(C) As viewed from the top, the overlapping
cytokine binding sites by IL-2Rα and IL-13Rα1 D1 domains are
apparent. Semitransparent ovals have been drawn around the D1
domain of IL-2Rα and IL-13Rα1 so that regions of overlap are
clear.
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The above figures are
reprinted
from an Open Access publication published by Cell Press:
Cell
(2008,
132,
259-272)
copyright 2008.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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C.Moriya,
M.Jinnin,
K.Yamane,
K.Maruo,
F.C.Muchemwa,
T.Igata,
T.Makino,
S.Fukushima,
and
H.Ihn
(2011).
Expression of matrix metalloproteinase-13 is controlled by IL-13 via PI3K/Akt3 and PKC-δ in normal human dermal fibroblasts.
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J Invest Dermatol,
131,
655-661.
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|
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D.C.Newcomb,
M.G.Boswell,
W.Zhou,
M.M.Huckabee,
K.Goleniewska,
C.M.Sevin,
G.K.Hershey,
J.K.Kolls,
and
R.S.Peebles
(2011).
Human TH17 cells express a functional IL-13 receptor and IL-13 attenuates IL-17A production.
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J Allergy Clin Immunol,
127,
1006.
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J.E.Allen,
and
R.M.Maizels
(2011).
Diversity and dialogue in immunity to helminths.
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Nat Rev Immunol,
11,
375-388.
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T.Eiwegger,
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M.Zimmermann,
and
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(2011).
Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases.
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J Allergy Clin Immunol,
127,
701.
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S.K.Madala,
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T.R.Ramalingam,
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D.C.Masison,
and
T.A.Wynn
(2011).
Mapping mouse IL-13 binding regions using structure modeling, molecular docking, and high-density peptide microarray analysis.
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Proteins,
79,
282-293.
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T.Wang,
W.Huang,
M.M.Costa,
S.A.Martin,
and
C.J.Secombes
(2011).
Two copies of the genes encoding the subunits of putative interleukin (IL)-4/IL-13 receptors, IL-4Rα, IL-13Rα1 and IL-13Rα2, have been identified in rainbow trout (Oncorhynchus mykiss) and have complex patterns of expression and modulation.
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Immunogenetics,
63,
235-253.
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|
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A.A.Kossiakoff,
and
S.Rizk
(2010).
Keeping signaling in check.
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Structure,
18,
275-276.
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A.E.Price,
H.E.Liang,
B.M.Sullivan,
R.L.Reinhardt,
C.J.Eisley,
D.J.Erle,
and
R.M.Locksley
(2010).
Systemically dispersed innate IL-13-expressing cells in type 2 immunity.
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Proc Natl Acad Sci U S A,
107,
11489-11494.
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B.G.Dewals,
R.G.Marillier,
J.C.Hoving,
M.Leeto,
A.Schwegmann,
and
F.Brombacher
(2010).
IL-4Ralpha-independent expression of mannose receptor and Ym1 by macrophages depends on their IL-10 responsiveness.
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PLoS Negl Trop Dis,
4,
e689.
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D.B.Trivella,
J.R.Ferreira-Júnior,
L.Dumoutier,
J.C.Renauld,
and
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(2010).
Structure and function of interleukin-22 and other members of the interleukin-10 family.
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Cell Mol Life Sci,
67,
2909-2935.
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F.L.Koller,
D.G.Hwang,
E.A.Dozier,
and
B.Fingleton
(2010).
Epithelial interleukin-4 receptor expression promotes colon tumor growth.
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Carcinogenesis,
31,
1010-1017.
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J.M.Daley,
S.K.Brancato,
A.A.Thomay,
J.S.Reichner,
and
J.E.Albina
(2010).
The phenotype of murine wound macrophages.
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J Leukoc Biol,
87,
59-67.
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J.M.Tarrant
(2010).
Blood cytokines as biomarkers of in vivo toxicity in preclinical safety assessment: considerations for their use.
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Toxicol Sci,
117,
4.
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|
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M.I.Siponen,
M.Wisniewska,
L.Lehtiö,
I.Johansson,
L.Svensson,
G.Raszewski,
L.Nilsson,
M.Sigvardsson,
and
H.Berglund
(2010).
Structural determination of functional domains in early B-cell factor (EBF) family of transcription factors reveals similarities to Rel DNA-binding proteins and a novel dimerization motif.
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J Biol Chem,
285,
25875-25879.
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PDB codes:
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M.Koyanagi,
J.A.Kerns,
L.Chung,
Y.Zhang,
S.Brown,
T.Moldoveanu,
H.S.Malik,
and
M.Bix
(2010).
Diversifying selection and functional analysis of interleukin-4 suggests antagonism-driven evolution at receptor-binding interfaces.
|
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BMC Evol Biol,
10,
223.
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P.J.Lupardus,
M.E.Birnbaum,
and
K.C.Garcia
(2010).
Molecular basis for shared cytokine recognition revealed in the structure of an unusually high affinity complex between IL-13 and IL-13Ralpha2.
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Structure,
18,
332-342.
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PDB code:
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R.J.Falconer,
A.Penkova,
I.Jelesarov,
and
B.M.Collins
(2010).
Survey of the year 2008: applications of isothermal titration calorimetry.
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J Mol Recognit,
23,
395-413.
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S.H.Liu,
C.N.Yang,
H.C.Pan,
Y.J.Sung,
K.K.Liao,
W.B.Chen,
W.Z.Lin,
and
M.L.Sheu
(2010).
IL-13 downregulates PPAR-gamma/heme oxygenase-1 via ER stress-stimulated calpain activation: aggravation of activated microglia death.
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Cell Mol Life Sci,
67,
1465-1476.
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S.Mirza,
A.Walker,
J.Chen,
J.M.Murphy,
and
I.G.Young
(2010).
The Ig-like domain of human GM-CSF receptor alpha plays a critical role in cytokine binding and receptor activation.
|
| |
Biochem J,
426,
307-317.
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Y.Loe-Mie,
A.M.Lepagnol-Bestel,
G.Maussion,
A.Doron-Faigenboim,
S.Imbeaud,
H.Delacroix,
L.Aggerbeck,
T.Pupko,
P.Gorwood,
M.Simonneau,
and
J.M.Moalic
(2010).
SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution.
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Hum Mol Genet,
19,
2841-2857.
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A.Q.Ford,
N.M.Heller,
L.Stephenson,
M.R.Boothby,
and
A.D.Keegan
(2009).
An atopy-associated polymorphism in the ectodomain of the IL-4R(alpha) chain (V50) regulates the persistence of STAT6 phosphorylation.
|
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J Immunol,
183,
1607-1616.
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B.Dewals,
J.C.Hoving,
M.Leeto,
R.G.Marillier,
U.Govender,
A.J.Cutler,
W.G.Horsnell,
and
F.Brombacher
(2009).
IL-4Ralpha responsiveness of non-CD4 T cells contributes to resistance in schistosoma mansoni infection in pan-T cell-specific IL-4Ralpha-deficient mice.
|
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Am J Pathol,
175,
706-716.
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C.A.McElroy,
J.A.Dohm,
and
S.T.Walsh
(2009).
Structural and biophysical studies of the human IL-7/IL-7Ralpha complex.
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Structure,
17,
54-65.
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PDB codes:
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C.C.Lewis,
B.Aronow,
J.Hutton,
J.Santeliz,
K.Dienger,
N.Herman,
F.D.Finkelman,
and
M.Wills-Karp
(2009).
Unique and overlapping gene expression patterns driven by IL-4 and IL-13 in the mouse lung.
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J Allergy Clin Immunol,
123,
795.
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F.O.Martinez,
L.Helming,
and
S.Gordon
(2009).
Alternative activation of macrophages: an immunologic functional perspective.
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Annu Rev Immunol,
27,
451-483.
|
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I.Moraga,
D.Harari,
G.Schreiber,
G.Uzé,
and
S.Pellegrini
(2009).
Receptor density is key to the alpha2/beta interferon differential activities.
|
| |
Mol Cell Biol,
29,
4778-4787.
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|
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J.Chen,
J.Olsen,
S.Ford,
S.Mirza,
A.Walker,
J.M.Murphy,
and
I.G.Young
(2009).
A New Isoform of Interleukin-3 Receptor {alpha} with Novel Differentiation Activity and High Affinity Binding Mode.
|
| |
J Biol Chem,
284,
5763-5773.
|
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L.K.Ely,
S.Fischer,
and
K.C.Garcia
(2009).
Structural basis of receptor sharing by interleukin 17 cytokines.
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Nat Immunol,
10,
1245-1251.
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PDB code:
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R.Dey,
K.Ji,
Z.Liu,
and
L.Chen
(2009).
A cytokine-cytokine interaction in the assembly of higher-order structure and activation of the interleukine-3:receptor complex.
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| |
PLoS ONE,
4,
e5188.
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T.Ito,
S.Suzuki,
S.Kanaji,
H.Shiraishi,
S.Ohta,
K.Arima,
G.Tanaka,
T.Tamada,
E.Honjo,
K.C.Garcia,
R.Kuroki,
and
K.Izuhara
(2009).
Distinct structural requirements for interleukin-4 (IL-4) and IL-13 binding to the shared IL-13 receptor facilitate cellular tuning of cytokine responsiveness.
|
| |
J Biol Chem,
284,
24289-24296.
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T.R.Hercus,
D.Thomas,
M.A.Guthridge,
P.G.Ekert,
J.King-Scott,
M.W.Parker,
and
A.F.Lopez
(2009).
The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease.
|
| |
Blood,
114,
1289-1298.
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V.Amanatidou,
S.Apostolakis,
and
D.A.Spandidos
(2009).
Genetic diversity of the host and severe respiratory syncytial virus-induced lower respiratory tract infection.
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Pediatr Infect Dis J,
28,
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X.Wang,
P.Lupardus,
S.L.Laporte,
and
K.C.Garcia
(2009).
Structural biology of shared cytokine receptors.
|
| |
Annu Rev Immunol,
27,
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X.Zhu,
W.D.Marcus,
W.Xu,
H.I.Lee,
K.Han,
J.O.Egan,
J.L.Yovandich,
P.R.Rhode,
and
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(2009).
Novel human interleukin-15 agonists.
|
| |
J Immunol,
183,
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I.S.Junttila,
K.Mizukami,
H.Dickensheets,
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and
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(2008).
Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac regulates relative cytokine sensitivity.
|
| |
J Exp Med,
205,
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|
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J.Gilmour,
and
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(2008).
Control of IL-4 expression in T helper 1 and 2 cells.
|
| |
Immunology,
124,
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|
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|
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N.M.Heller,
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I.S.Junttila,
K.A.Shirey,
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W.E.Paul,
and
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(2008).
Type I IL-4Rs selectively activate IRS-2 to induce target gene expression in macrophages.
|
| |
Sci Signal,
1,
ra17.
|
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|
|
|
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P.J.Lupardus,
and
K.C.Garcia
(2008).
The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12.
|
| |
J Mol Biol,
382,
931-941.
|
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
