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PDBsum entry 4mxw
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Cytokine/immune system
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PDB id
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4mxw
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Contents |
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79 a.a.
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134 a.a.
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131 a.a.
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134 a.a.
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149 a.a.
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212 a.a.
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211 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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Dimerization of ltβr by ltα1β2 is necessary and sufficient for signal transduction.
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Authors
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J.Sudhamsu,
J.Yin,
E.Y.Chiang,
M.A.Starovasnik,
J.L.Grogan,
S.G.Hymowitz.
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Ref.
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Proc Natl Acad Sci U S A, 2013,
110,
19896-19901.
[DOI no: ]
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PubMed id
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Abstract
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Homotrimeric TNF superfamily ligands signal by inducing trimers of their cognate
receptors. As a biologically active heterotrimer, Lymphotoxin(LT)α1β2 is
unique in the TNF superfamily. How the three unique potential receptor-binding
interfaces in LTα1β2 trigger signaling via LTβ Receptor (LTβR) resulting in
lymphoid organogenesis and propagation of inflammatory signals is poorly
understood. Here we show that LTα1β2 possesses two binding sites for LTβR
with distinct affinities and that dimerization of LTβR by LTα1β2 is necessary
and sufficient for signal transduction. The crystal structure of a complex
formed by LTα1β2, LTβR, and the fab fragment of an antibody that blocks LTβR
activation reveals the lower affinity receptor-binding site. Mutations targeting
each potential receptor-binding site in an engineered single-chain variant of
LTα1β2 reveal the high-affinity site. NF-κB reporter assays further validate
that disruption of receptor interactions at either site is sufficient to prevent
signaling via LTβR.
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