Chang B S, Minn A J, Muchmore S W, Fesik S W, Thompson C B
Department of Medicine, The University of Chicago, IL 60637, USA.
EMBO J. 1997 Mar 3;16(5):968-77. doi: 10.1093/emboj/16.5.968.
Bcl-X(L), a member of the Bcl-2 family, can inhibit many forms of programed cell death. The three-dimensional structure of Bcl-X(L) 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-X(L) 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-X(L) and Bcl-2 can suppress the anti-apoptotic function of these genes and may be a target for regulatory post-translational modifications.
Bcl-X(L)是Bcl-2家族的一员，能够抑制多种形式的程序性细胞死亡。Bcl-X(L)的三维结构确定了一个缺乏明确结构的60个氨基酸的环。尽管该区域内的氨基酸序列在Bcl-2家族成员中并不保守，但结构建模表明Bcl-2也包含一个大的无结构区域。与全长蛋白相比，Bcl-X(L)和Bcl-2的环缺失突变体表现出增强的抑制细胞凋亡的能力。尽管功能增强，但缺失突变体在结合促凋亡蛋白（如Bax）的能力上没有显著改变。Bcl-2的环缺失突变体在抑制细胞凋亡的能力上也表现出质的差异。全长Bcl-2无法阻止抗IgM诱导的未成熟B细胞系WEHI-231的细胞死亡。相比之下，Bcl-2缺失突变体保护WEHI-231细胞免于死亡。与全长Bcl-2相比，观察到WEHI-231细胞磷酸化Bcl-2缺失突变体的能力存在显著差异。发现Bcl-2磷酸化依赖于完整环结构域的存在。这些结果表明，Bcl-X(L)和Bcl-2中的环结构域可以抑制这些基因的抗凋亡功能，并且可能是翻译后调控修饰的靶点。
