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PDBsum entry 2n83
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Signaling protein/transferase
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PDB id
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2n83
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References listed in PDB file
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Key reference
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Title
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Structural basis of death domain signaling in the p75 neurotrophin receptor.
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Authors
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Z.Lin,
J.Y.Tann,
E.T.Goh,
C.Kelly,
K.B.Lim,
J.F.Gao,
C.F.Ibanez.
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Ref.
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Elife, 2015,
4,
e11692.
[DOI no: ]
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PubMed id
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Abstract
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Death domains (DDs) mediate assembly of oligomeric complexes for activation of
downstream signaling pathways through incompletely understood mechanisms. Here
we report structures of complexes formed by the DD of p75 neurotrophin receptor
(p75(NTR)) with RhoGDI, for activation of the RhoA pathway, with caspase
recruitment domain (CARD) of RIP2 kinase, for activation of the NF-kB pathway,
and with itself, revealing how DD dimerization controls access of intracellular
effectors to the receptor. RIP2 CARD and RhoGDI bind to p75(NTR) DD at partially
overlapping epitopes with over 100-fold difference in affinity, revealing the
mechanism by which RIP2 recruitment displaces RhoGDI upon ligand binding. The
p75(NTR) DD forms non-covalent, low-affinity symmetric dimers in solution. The
dimer interface overlaps with RIP2 CARD but not RhoGDI binding sites, supporting
a model of receptor activation triggered by separation of DDs. These structures
reveal how competitive protein-protein interactions orchestrate the hierarchical
activation of downstream pathways in non-catalytic receptors.
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