CD40 is a member of the tumor necrosis factor (TNF) receptor family. CD40-mediated signal transduction involves the recruitment of several cytoplasmic proteins and induces expression of a large number of genes. TTRAP, a novel protein that interacts with the cytoplasmic domain of CD40 and with TNF-receptor associated factors (TRAFs), has been cloned and shown to inhibit nuclear factor-kappaB activation (NF-kappaB). By using various bioinformatics-based sequence and structure analyses of proteins involved in signaling by the TNF receptor family, we found that TTRAP is a member of a superfamily of Mg2+/Mn2+-dependent phosphodiesterases. More precisely, our results suggest that TTRAP is related to the human APE I, a Mg2+-dependent endonuclease. This potential novel function of TTRAP raises the intriguing possibility for a role of APE1-like DNA-repair endonucleases in TNT receptor family-mediated signaling and functions.