The adenovirus E1B 19 kDa protein provides a cell survival function during adenovirus infection and facilitates efficient virus replication by preventing premature cell death. These functions resemble those performed by the protein coded by the proto-oncogene Bcl-1. The Bcl-1 protein, which provides a survival function in cells exposed to a number of cell death-inducing stimuli, can substitute for the 19 kDa protein during adenovirus infection. Although these two survival- promoting proteins are not overtly related by primary amino acid sequence, they appear to share short homologous sequences. In order to determine if these sequence motifs constitute common functional domains, we carried out domain exchanges between the 19 kDa and Bcl-2 proteins. Our results indicate that a seven amino acid region of the Bcl-2 protein (108-YRRDFAE-114) can efficiently substitute for the corresponding 19 kDa domain (47-YKWEFEE-53). Mutagenizing this domain in Bcl-2 abolishes the survival promoting activity of Bcl-2. Substitution of the kDa sequences into Bcl-2 restores the survival promoting activity, albeit at reduced levels. Our results suggest that this domain (designated NH1) may constitute a common functional domain for the 19 kDa protein and survival promoting members of the Bcl-2 family of proteins.