8WWY

Crystal structure of mouse TIFA/TIFAB heterodimer

Summary for 8WWY

• Entry DOI: 10.2210/pdb8wwy/pdb
• Descriptor: TRAF-interacting protein with FHA domain-containing protein A, TRAF-interacting protein with FHA domain-containing protein B, (2R,5R)-hexane-2,5-diol, ... (4 entities in total)
• Functional Keywords: complex, signaling protein
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 4
• Total formula weight: 67962.50

Authors

Nakamura, T. (deposition date: 2023-10-27, release date: 2024-03-13)

Primary citation

Nakamura, T.,Ohyama, C.,Sakamoto, M.,Toma, T.,Tateishi, H.,Matsuo, M.,Chirifu, M.,Ikemizu, S.,Morioka, H.,Fujita, M.,Inoue, J.I.,Yamagata, Y.
TIFAB regulates the TIFA-TRAF6 signaling pathway involved in innate immunity by forming a heterodimer complex with TIFA.
Proc.Natl.Acad.Sci.USA, 121:e2318794121-e2318794121, 2024

PubMed Abstract: Nuclear factor κB (NF-κB) is activated by various inflammatory and infectious molecules and is involved in immune responses. It has been elucidated that ADP-β-D-manno-heptose (ADP-Hep), a metabolite in gram-negative bacteria, activates NF-κB through alpha-kinase 1 (ALPK1)-TIFA-TRAF6 signaling. ADP-Hep stimulates the kinase activity of ALPK1 for TIFA phosphorylation. Complex formation between phosphorylation-dependent TIFA oligomer and TRAF6 promotes the polyubiquitination of TRAF6 for NF-κB activation. TIFAB, a TIFA homolog lacking a phosphorylation site and a TRAF6 binding motif, is a negative regulator of TIFA-TRAF6 signaling and is implicated in myeloid diseases. TIFAB is indicated to regulate TIFA-TRAF6 signaling through interactions with TIFA and TRAF6; however, little is known about its biological function. We demonstrated that TIFAB forms a complex not with the TIFA dimer, an intrinsic form of TIFA involved in NF-κB activation, but with monomeric TIFA. The structural analysis of the TIFA/TIFAB complex and the biochemical and cell-based analyses showed that TIFAB forms a stable heterodimer with TIFA, inhibits TIFA dimer formation, and suppresses TIFA-TRAF6 signaling. The resultant TIFA/TIFAB complex is a "pseudo-TIFA dimer" lacking the phosphorylation site and TRAF6 binding motif in TIFAB and cannot form the orderly structure as proposed for the phosphorylated TIFA oligomer involved in NF-κB activation. This study elucidated the molecular and structural basis for the regulation of TIFA-TRAF6 signaling by TIFAB.

PubMed: 38442163
DOI: 10.1073/pnas.2318794121

Experimental method

X-RAY DIFFRACTION (1.79 Å)