Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2
Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2
复制标题
DOI：
10.7554/elife.37689
复制
发表时间：
2019-03-12
期刊：
影响因子：
7.7
通讯作者：
Andrews, David William
中科院分区：
文献类型：
--
作者：
Liu, Qian;Oesterlund, Elizabeth J.;Andrews, David William
肿瘤的发生、发展和对化疗的抵抗依赖于癌细胞通过凋亡绕过程序性细胞死亡。我们报告说，与其他促凋亡蛋白，Bim包含两个不同的结合位点的抗凋亡蛋白Bcl-XL和Bcl-2。这些包括与其他促凋亡蛋白共有的BH 3序列和位于Bim羧基末端附近的意外序列（残基181-192）。使用自动荧光寿命成像显微镜-荧光共振能量转移（FLIM-FRET），我们表明，这两个结合界面使Bim能够双螺栓锁定Bcl-XL和Bcl-2的复合物抵抗目前使用或正在评估的BH 3模拟药物的替代癌症治疗。在活细胞中定量单个氨基酸的贡献揭示了先前认为参与Bim与膜结合的残基L185，而不是有助于与抗凋亡蛋白结合。这种双螺栓锁定机制对BH 3模拟物作为药物的效用具有深远的影响。
Tumor initiation, progression and resistance to chemotherapy rely on cancer cells bypassing programmed cell death by apoptosis. We report that unlike other pro-apoptotic proteins, Bim contains two distinct binding sites for the anti-apoptotic proteins Bcl-XL and Bcl-2. These include the BH3 sequence shared with other pro-apoptotic proteins and an unexpected sequence located near the Bim carboxyl-terminus (residues 181-192). Using automated Fluorescence Lifetime Imaging Microscopy - Fluorescence Resonance Energy Transfer (FLIM-FRET) we show that the two binding interfaces enable Bim to double-bolt lock Bcl-XL and Bcl-2 in complexes resistant to displacement by BH3-mimetic drugs currently in use or being evaluated for cancer therapy. Quantifying in live cells the contributions of individual amino acids revealed that residue L185 previously thought involved in binding Bim to membranes, instead contributes to binding to anti-apoptotic proteins. This double-bolt lock mechanism has profound implications for the utility of BH3-mimetics as drugs.