Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity

Teruya Nakamura, Chie Hashikawa, Kohtaro Okabe, Yuya Yokote, Mami Chirifu, Sachiko Toma-Fukai, Narushi Nakamura, Mihoko Matsuo, Miho Kamikariya, Yoshinari Okamoto, Jin Gohda, Taishin Akiyama, Kentaro Semba, Shinji Ikemizu, Masami Otsuka, Jun ichiro Inoue, Yuriko Yamagata

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number5152
JournalScientific reports
Volume10
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

ASJC Scopus subject areas

  • General

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