TWEAK binding to the Fn14 cysteine-rich domain depends on charged residues located in both the A1 and D2 modules

The Biochemical Journal
Sharron A N BrownJeffrey A Winkles

Abstract

TWEAK [TNF (tumour necrosis factor)-like weak inducer of apoptosis] is a member of the TNF superfamily of cytokines. TWEAK binds with high affinity to a single TNF receptor super-family member, Fn14 (fibroblast growth factor-inducible 14). This interaction can stimulate a variety of biological responses, depending on the cell type analysed. The murine Fn14 extracellular region is only 53 amino acids in length and primarily consists of a CRD (cysteine-rich domain) containing three disulphide bonds. In the present study, we investigated whether TWEAK binding to this CRD was dependent on selected evolutionarily conserved amino acid residues by using a site-specific mutagenesis approach and several different ligand-binding assays. Our results indicate that three residues within the predicted Fn14 CRD A1 module (Asp45, Lys48 and Met50) and one residue within the predicted D2 module (Asp62) are each critical for high-affinity TWEAK binding. Mutation of the three charged polar residues Asp45, Lys48 and Asp62 had the greatest deleterious effect, suggesting that electrostatic interactions between TWEAK and Fn14 residues may be particularly important for complex formation or stability. To determine whether the four critical residues were...Continue Reading

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