Sequence analysis identifies TTRAP, a protein that associates with CD40 and TNF receptor-associated factors, as a member of a superfamily of divalentcation-dependent phosphodiesterases

CD40 is a member of the tumor necrosis factor (TNF) receptor family. CD40-m ediated 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-re ceptor associated factors (TRAFs), has been cloned and shown to inhibit nuc lear 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 o f Mg2+/Mn2+-dependent phosphodiesterases. More precisely, our results sugge st that TTRAP is related to the human APE I, a Mg2+-dependent endonuclease. This potential novel function of TTRAP raises the intriguing possibility f or a role of APE1-like DNA-repair endonucleases in TNT receptor family-medi ated signaling and functions. (C) 2001 Academic Press.