Binding and Enhanced Binding between Key Immunity Proteins TRAF6 and TIFA
Journal
ChemBioChem
Journal Volume
20
Journal Issue
2
Pages
140-146
Date Issued
2019
Author(s)
Abstract
Human tumor necrosis factor receptor associated factor (TRAF)-interacting protein, with a forkhead-associated domain (TIFA), is a key regulator of NF-κB activation. It also plays a key role in the activation of innate immunity in response to bacterial infection, through heptose 1,7-bisphosphate (HBP); a metabolite of lipopolysaccharide (LPS). However, the mechanism of TIFA function is largely unexplored, except for the suggestion of interaction with TRAF6. Herein, we provide evidence for direct binding, albeit weak, between TIFA and the TRAF domain of TRAF6, and it is shown that the binding is enhanced for a rationally designed double mutant, TIFA S174Q/M179D. Enhanced binding was also demonstrated for endogenous full-length TRAF6. Furthermore, the structures of the TRAF domain complexes with the consensus TRAF-binding peptides from the C terminus of wild-type and S174Q/M179D mutant TIFA, showing salt-bridge formation between residues 177–181 of TIFA and the binding pocket residues of the TRAF domain, were solved. Taken together, the results provide direct evidence and a structural basis for the TIFA–TRAF6 interaction, and show how this important biological function can be modulated. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Subjects
biological activity; mutagenesis; noncovalent interactions; protein–protein interactions; structure elucidation
Other Subjects
carrier proteins and binding proteins; peptide; TIFA protein; tumor necrosis factor receptor associated factor; unclassified drug; signal transducing adaptor protein; T2BP protein, human; Tifab protein, human; tumor necrosis factor receptor associated factor 6; Article; biological activity; carboxy terminal sequence; complex formation; controlled study; human; human cell; immune response; immunity; priority journal; protein binding; protein protein interaction; protein purification; protein structure; residue analysis; wild type; binding site; chemistry; genetics; HEK293 cell line; metabolism; protein conformation; Adaptor Proteins, Signal Transducing; Binding Sites; HEK293 Cells; Humans; Protein Conformation; TNF Receptor-Associated Factor 6
Type
journal article