Role of membrane anchor domain of Bcl-2 in suppression of apoptosis caused by E1B-defective adenovirus.

Bcl-2 is an integral membrane protein that functions as a suppressor of programmed cell death. It contains a COOH-terminal signal anchor sequence that is selective for import and insertion of Bcl-2 into the mitochondrial outer membrane and, by a different mechanism, can also direct the protein to other membrane sites. Deletion of the signal anchor sequence rendered Bcl-2 cytosolic and impaired its ability to prevent apoptotic death of human KB cells infected with a mutant form of adenovirus type 5 that does not make E1B 19-kDa protein. When the predicted transmembrane domain of the Bcl-2 signal anchor was replaced with that of the signal anchor of the yeast outer mitochondrial membrane protein, Mas70p, the Bcl-2/Mas70p hybrid was found to be very similar to Bcl-2 in its distribution within transfected KB cells, in its ability to heterodimerize with Bax, and in its ability to suppress apoptosis. These results are consistent with a model in which the transmembrane segment contributes to the function of Bcl-2 by targeting and anchoring the protein to strategic membrane locations in the cell. Concentration of Bcl-2 at these sites may contribute to its proposed role as regulator, or component, of an antioxidant pathway.