SnapShot: BCL-2 proteins.
SnapShot: BCL-2 proteins.
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DOI：
10.1016/j.cell.2009.07.003
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发表时间：
2009-07-23
期刊：
影响因子：
64.5
通讯作者：
Youle RJ
中科院分区：
文献类型：
--
作者：
Hardwick JM;Youle RJ
BCL-2家族蛋白调节凋亡性细胞死亡。BCL-2蛋白定位于细胞内膜如内质网和线粒体，并且一些家族成员在细胞死亡刺激后从细胞质易位到线粒体。Bcl-2家族的典型成员Bcl-2最初在人类滤泡性淋巴瘤的染色体易位断点处被鉴定，随后被证明通过抑制细胞死亡而不是通过促进细胞周期进程来促进肿瘤发生。一般类别包括多结构域抗凋亡蛋白（BH 1-BH 4）、多结构域促凋亡蛋白（BH 1-BH 3）和促凋亡蛋白（仅BH 3）（见表1）。在传统观点中，健康细胞中的抗死亡BCL-2家族成员控制着促死亡BCL-2家族成员。在接受死亡刺激后，BH 3-only蛋白会破坏保护性BCL-2蛋白，迫使它们释放亲死亡伙伴。这些促死亡BCL-2家族蛋白同源寡聚化以在线粒体外膜中产生孔，导致细胞色素c释放到细胞质中，这导致半胱天冬酶活化和细胞死亡。另一种模型表明，抗死亡BCL-2蛋白结合并抑制BH 3-only蛋白（例如BID）的一个子集，否则直接诱导BAX或巴克的寡聚化。然而，并非所有可用的数据都与这些模型一致，并且一些家族成员似乎缺乏细胞死亡调节功能。因此，BCL-2家族蛋白也可以根据其氨基酸相似性和三维结构进行分类（见表2）。人们越来越关注BCL-2家族蛋白的替代作用机制，包括线粒体动力学、自噬、能量学和其他功能的调节。在秀丽隐杆线虫中存在三种BCL-2相关蛋白，包括CED-9、EGL-1和CED-13。CED-9是存活所必需的，抑制CED-4介导的CED-3（半胱天冬酶）活化，并且在细胞死亡期间被仅含BH 3的蛋白EGL-1和CED-13抑制; CED-9可以表现出促死亡活性并且可以调节线粒体动力学。果蝇Drosophila melanogaster编码两个BCL-2家族蛋白。这些在细胞死亡中的功能尚不确定。病毒BCL-2样蛋白由不同类型的DNA病毒编码，包括未列出的实例。许多病毒BCL-2样蛋白抑制凋亡性细胞死亡，但其他蛋白可能在感染过程中通过替代功能改变其动物宿主和宿主细胞。已经在许多BCL-2家族蛋白的N-末端区域中鉴定了蛋白酶切割位点，包括BCL-2、BCL-xL、MCL-1、BAX、BID（切割以产生具有暴露的BH 3结构域的截短的tBID）和BAD。裂解可以抑制抗死亡活性或激活促死亡活性。所有指定蛋白质的三维结构可在Protein Data Bank（PDB）（http：//www. rcsb. org/pdb/home/home. do）以及BAD、BNIP 3L和Beclin的另外的结构域结构。其他可用的结构包括Beclin/Atg 6/Vps 30中与BCL-2的裂缝结合的BH 3基序和病毒gHV 68 BCL-2同源物M11的结构。BNIP 3属于不同的蛋白质家族。
BCL-2 family proteins regulate apoptotic cell death. BCL-2 proteins localize to intracellular membranes such as endoplasmic reticulum and mitochondria, and some family members translocate from the cytoplasm to mitochondria following a cell death stimulus. The prototypical family member Bcl-2 was originally identified at chromosome translocation breakpoints in human follicular lymphoma and was subsequently shown to promote tumorigenesis by inhibiting cell death rather than by promoting cell-cycle progression.BCL-2 family proteins have traditionally been classified according to their function and their BCL-2 homology (BH) motifs. The general categories include multidomain antiapoptotic proteins (BH1-BH4), multidomain proapoptotic proteins (BH1-BH3), and proapoptotic BH3-only proteins (see Table 1). In the traditional view, anti-death BCL-2 family members in healthy cells hold pro-death BCL-2 family members in check. Upon receiving a death stimulus, BH3-only proteins inactivate the protective BCL-2 proteins, forcing them to release their pro-death partners. These pro-death BCL-2 family proteins homo-oligomerize to create pores in the mitochondrial outer membrane, resulting in cytochrome c release into the cytoplasm, which leads to caspase activation and cell death. An alternative model suggests that anti-death BCL-2 proteins bind and inhibit a subset of BH3-only proteins (eg, BID) that otherwise directly induce the oligomerization of BAX or BAK. However, not all available data are consistent with these models, and some family members appear to lack cell death regulatory functions. Therefore, BCL-2 family proteins can also be classified based on their amino acid similarities and three-dimensional structures (see Table 2). Growing attention is being paid to alternative mechanisms of action for BCL-2 family proteins, including the regulation of mitochondrial dynamics, autophagy, energetics, and other functions. There are three BCL-2-related proteins in the nematode Caenorhabditis elegans, including CED-9, EGL-1, and CED-13. CED-9 is required for survival, inhibits CED-4-mediated activation of CED-3 (a caspase), and is inhibited by the BH3-only proteins EGL-1 and CED-13 during cell death; CED-9 can exhibit pro-death activity and may regulate mitochondrial dynamics. The fruit fly Drosophila melanogaster encodes two BCL-2 family proteins. The functions of these in cell death are uncertain. Viral BCL-2-like proteins are encoded by different types of DNA viruses, including examples not listed. Many viral BCL-2-like proteins inhibit apoptotic cell death, but others may alter their animal hosts and host cells during the course of infection by alternative functions. Protease cleavage sites have been identified in the N-terminal regions of a number of BCL-2 family proteins, including BCL-2, BCL-xL, MCL-1, BAX, BID (cleaved to generate truncated tBID with exposed BH3 domain), and BAD. Cleavage may inactivate anti-death activity or activate pro-death activity. Three-dimensional structures for all indicated proteins are found at the Protein Data Bank (PDB)(http://www. rcsb. org/pdb/home/home. do) as are additional domain structures for BAD, BNIP3L, and Beclin. Other available structures include a BH3 motif in Beclin/Atg6/Vps30 binding to the cleft of BCL-2 and a structure of the viral gHV68 BCL-2 homolog M11. BNIP3 belongs to a different protein family.