The human Taci gene (Transmembrane Activator and CAML Interactor) encodes a recently discovered member of the Tumor Necrosis Factor Receptor family. TACI is expressed in B-lymphocytes and may act to regulate humoral immunity. To identify functionally important regions of the protein, we have isolated and characterized the murine homolog of the human Taci cDNA. The proteins display 61.5% similarity and 54.6% identity. Mouse TACI is a type III transmembrane protein, as judged by the lack of a cleaved signal sequence and its N-terminal extracellular exposure. The intracellular domains of the mouse and human proteins share a single, defined region of high sequence conservation (19 of 23 residues identical). This constitutes a novel domain that may play a part in the initiation of signal transduction through TACI. In support of this notion, mouse TACI was found to activate NFAT, NFkB, and AP1 transcription factors in a transient transfection assay. The Taci gene was localized to human Chromosome (Chr) 17p11 by fluorescence in situ hybridization. The murine homolog was localized by intraspecific backcross analysis to the middle of Chr 11, a region that is syntenic to human Chr 17p. This work identifies conserved domains within TACI that may mediate the cellular distribution and signal transduction function of the protein and extend the details of homology between mouse Chr 11 and human 17p.