Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Humans
Immunity, Innate
/ immunology
Intracellular Signaling Peptides and Proteins
/ metabolism
Mice
NF-kappa B
/ metabolism
Pathogen-Associated Molecular Pattern Molecules
/ immunology
Phosphorylation
Protein Kinases
/ metabolism
Signal Transduction
/ physiology
TNF Receptor-Associated Factor 6
/ metabolism
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
/ metabolism
Ubiquitination
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
20 03 2020
20 03 2020
Historique:
received:
11
11
2019
accepted:
03
03
2020
entrez:
22
3
2020
pubmed:
22
3
2020
medline:
7
1
2021
Statut:
epublish
Résumé
TRAF-interacting protein with a forkhead-associated (FHA) domain (TIFA), originally identified as an adaptor protein of TRAF6, has recently been shown to be involved in innate immunity, induced by a pathogen-associated molecular pattern (PAMP). ADP-β-D-manno-heptose, a newly identified PAMP, binds to alpha-kinase 1 (ALPK1) and activates its kinase activity to phosphorylate TIFA. Phosphorylation triggers TIFA oligomerisation and formation of a subsequent TIFA-TRAF6 oligomeric complex for ubiquitination of TRAF6, eventually leading to NF-κB activation. However, the structural basis of TIFA-dependent TRAF6 signalling, especially oligomer formation of the TIFA-TRAF6 complex remains unknown. In the present study, we determined the crystal structures of mouse TIFA and two TIFA mutants-Thr9 mutated to either Asp or Glu to mimic the phosphorylation state-to obtain the structural information for oligomer formation of the TIFA-TRAF6 complex. Crystal structures show the dimer formation of mouse TIFA to be similar to that of human TIFA, which was previously reported. This dimeric structure is consistent with the solution structure obtained from small angle X-ray scattering analysis. In addition to the structural analysis, we examined the molecular assembly of TIFA and the TIFA-TRAF6 complex by size-exclusion chromatography, and suggested a model for the TIFA-TRAF6 signalling complex.
Identifiants
pubmed: 32198460
doi: 10.1038/s41598-020-61972-6
pii: 10.1038/s41598-020-61972-6
pmc: PMC7083832
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Intracellular Signaling Peptides and Proteins
0
NF-kappa B
0
Pathogen-Associated Molecular Pattern Molecules
0
TNF Receptor-Associated Factor 6
0
Tifab protein, human
0
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
0
Protein Kinases
EC 2.7.-
ALPK1 protein, human
EC 2.7.11.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5152Références
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