Identification of a novel regulatory domain in Bcl-xL and Bcl-2

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Abstract
Bcl‐xL, a member of the Bcl‐2 family, can inhibit many forms of programed cell death. The three‐dimensional structure of Bcl‐xL identified a 60 amino acid loop lacking defined structure. Although amino acid sequence within this region is not conserved among Bcl‐2 family members, structural modeling suggested that Bcl‐2 also contains a large unstructured region. Compared with the full‐length protein, loop deletion mutants of Bcl‐xL and Bcl‐2 displayed an enhanced ability to inhibit apoptosis. Despite enhanced function, the deletion mutants did not have significant alterations in the ability to bind pro‐apoptotic proteins such as Bax. The loop deletion mutant of Bcl‐2 also displayed a qualitative difference in its ability to inhibit apoptosis. Full‐length Bcl‐2 was unable to prevent anti‐IgM‐induced cell death of the immature B cell line WEHI‐231. In contrast, the Bcl‐2 deletion mutant protected WEHI‐231 cells from death. Substantial differences were observed in the ability of WEHI‐231 cells to phosphorylate the deletion mutant of Bcl‐2 compared with full‐length Bcl‐2. Bcl‐2 phosphorylation was found to be dependent on the presence of an intact loop domain. These results suggest that the loop domain in Bcl‐xL and Bcl‐2 can suppress the anti‐apoptotic function of these genes and may be a target for regulatory post‐translational modifications.