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PDBsum entry 4zgi
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Signaling protein
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PDB id
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4zgi
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References listed in PDB file
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Key reference
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Title
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Uncovering the mechanism of forkhead-Associated domain-Mediated tifa oligomerization that plays a central role in immune responses.
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Authors
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J.H.Weng,
Y.C.Hsieh,
C.C.Huang,
T.Y.Wei,
L.H.Lim,
Y.H.Chen,
M.R.Ho,
I.Wang,
K.F.Huang,
C.J.Chen,
M.D.Tsai.
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Ref.
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Biochemistry, 2015,
54,
6219-6229.
[DOI no: ]
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PubMed id
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Abstract
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Forkhead-associated (FHA) domain is the only signaling domain that recognizes
phosphothreonine (pThr) specifically. TRAF-interacting protein with an FHA
domain (TIFA) was shown to be involved in immune responses by binding with TRAF2
and TRAF6. We recently reported that TIFA is a dimer in solution and that, upon
stimulation by TNF-α, TIFA is phosphorylated at Thr9, which triggers TIFA
oligomerization via pThr9-FHA domain binding and activates nuclear factor κB
(NF-κB). However, the structural mechanism for the functionally important TIFA
oligomerization remains to be established. While FHA domain-pThr binding is
known to mediate protein dimerization, its role in oligomerization has not been
demonstrated at the structural level. Here we report the crystal structures of
TIFA (residues 1-150, with the unstructured C-terminal tail truncated) and its
complex with the N-terminal pThr9 peptide (residues 1-15), which show unique
features in the FHA structure (intrinsic dimer and extra β-strand) and in its
interaction with the pThr peptide (with residues preceding rather than following
pThr). These structural features support previous and additional functional
analyses. Furthermore, the structure of the complex suggests that the pThr9-FHA
domain interaction can occur only between different sets of dimers rather than
between the two protomers within a dimer, providing the structural mechanism for
TIFA oligomerization. Our results uncover the mechanism of FHA domain-mediated
oligomerization in a key step of immune responses and expand the paradigm of FHA
domain structure and function.
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