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PDBsum entry 5e4e
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Signaling protein
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PDB id
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5e4e
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Contents |
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111 a.a.
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183 a.a.
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303 a.a.
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References listed in PDB file
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Key reference
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Title
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Instructive roles for cytokine-Receptor binding parameters in determining signaling and functional potency.
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Authors
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I.Moraga,
D.Richter,
S.Wilmes,
H.Winkelmann,
K.Jude,
C.Thomas,
M.M.Suhoski,
E.G.Engleman,
J.Piehler,
K.C.Garcia.
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Ref.
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Sci Signal, 2015,
8,
ra114.
[DOI no: ]
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PubMed id
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Abstract
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Cytokines dimerize cell surface receptors to activate signaling and regulate
many facets of the immune response. Many cytokines have pleiotropic effects,
inducing a spectrum of redundant and distinct effects on different cell types.
This pleiotropy has hampered cytokine-based therapies, and the high doses
required for treatment often lead to off-target effects, highlighting the need
for a more detailed understanding of the parameters controlling cytokine-induced
signaling and bioactivities. Using the prototypical cytokine interleukin-13
(IL-13), we explored the interrelationships between receptor binding and a wide
range of downstream cellular responses. We applied structure-based engineering
to generate IL-13 variants that covered a spectrum of binding strengths for the
receptor subunit IL-13Rα1. Engineered IL-13 variants representing a broad range
of affinities for the receptor exhibited similar potencies in stimulating the
phosphorylation of STAT6 (signal transducer and activator of transcription 6).
Delays in the phosphorylation and nuclear translocation of STAT6 were only
apparent for those IL-13 variants with markedly reduced affinities for the
receptor. From these data, we developed a mechanistic model that quantitatively
reproduced the kinetics of STAT6 phosphorylation for the entire spectrum of
binding affinities. Receptor endocytosis played a key role in modulating STAT6
activation, whereas the lifetime of receptor-ligand complexes at the plasma
membrane determined the potency of the variant for inducing more distal
responses. This complex interrelationship between extracellular ligand binding
and receptor function provides the foundation for new mechanism-based strategies
that determine the optimal cytokine dose to enhance therapeutic efficacy.
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