TAPA-1 (the target of an antiproliferative antibody) is a 26-kDa cell surface protein expressed on most human cell lines. TAPA-1 is a member of an evolutionarily related family of cell surface proteins all of which contain four transmembrane domains. A model is proposed for topology of TAPA-1 based on proteolysis studies in the in vitro translated protein embedded into microsomal membranes. This analysis predicts that the amino and the carboxyl termini of the molecule are cytoplasmic and that the two hydrophilic regions of the molecule are extracellular. The antigenic epitope of the human TAPA-1 is contained within a subregion of the second extracellular domain of the protein. This is the only region in the protein that has not been tightly conserved in mammalian evolution.