Redefining the BH3 Death Domain as a 'Short Linear Motif'.
Redefining the BH3 Death Domain as a 'Short Linear Motif'.
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DOI：
10.1016/j.tibs.2015.09.007
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发表时间：
2015-12
影响因子：
13.8
通讯作者：
Hardwick, J. Marie
中科院分区：
文献类型：
--
作者：
Aouacheria, Abdel;Combet, Christophe;Tompa, Peter;Hardwick, J. Marie
B细胞淋巴瘤-2（BCL-2）相关蛋白通过BCL-2同源3（BH 3）结构域介导的蛋白-蛋白相互作用的复杂网络控制程序性细胞死亡。由于它们作为动态关键蛋白的作用，新的含BH 3蛋白的发现引起了相当大的关注。然而，由于没有一个明确定义的BH 3特征序列，BCL-2家族已经扩展到包括一组模糊的非同源BH 3蛋白质，现在通过一个有趣的转折来证明。我们提出的证据表明，从有序和无序的蛋白质BH 3代表了一类新的短线性图案（SLiMs）或分子识别功能（MoRFs），并在其进化历史是不同的。暗示的推论是，BH 3具有广泛的系统发育分布，并可能与具有不同功能的非BCL-2样结构域结合。BCL-2家族相互作用由进化上不同的BH 3基序介导以调节细胞凋亡。考虑到它们的关键作用，BH 3模拟物作为癌症疗法正在临床试验中。新的BH 3-only蛋白的发现代表了细胞死亡领域的一项重大奋进。因此，据报道，BH 3基序存在于不同蛋白质的模糊聚集体中，包括结构化的和内在无序的。BH 3基序没有严格的定义。目前可用的BH 3标签是多样的，难以预测新的功能性含BH 3的蛋白质。将BH 3基序重新定义为一种新型的短线性基序（SLiM）或分子识别特征（MoRF），调和了该基序的许多令人困惑的特征，并开辟了新的研究途径。
B cell lymphoma-2 (BCL-2)-related proteins control programmed cell death through a complex network of protein–protein interactions mediated by BCL-2 homology 3 (BH3) domains. Given their roles as dynamic linchpins, the discovery of novel BH3-containing proteins has attracted considerable attention. However, without a clearly defined BH3 signature sequence the BCL-2 family has expanded to include a nebulous group of nonhomologous BH3-only proteins, now justified by an intriguing twist. We present evidence that BH3s from both ordered and disordered proteins represent a new class of short linear motifs (SLiMs) or molecular recognition features (MoRFs) and are diverse in their evolutionary histories. The implied corollaries are that BH3s have a broad phylogenetic distribution and could potentially bind to non-BCL-2-like structural domains with distinct functions. BCL-2 family interactions are mediated by evolutionarily diverse BH3 motifs to regulate apoptosis. Given their key roles, BH3 mimetics are in clinical trials as cancer therapies. The discovery of novel BH3-only proteins represents a major endeavor in the cell death field. As a result, BH3 motifs are reportedly present in a nebulous conglomerate of different proteins, both structured and intrinsically disordered. There is no rigorous definition of a BH3 motif. Currently available BH3 signatures are diverse and elusive for predicting new functional BH3-containing proteins. Redefining the BH3 motif as a new type of short linear motif (SLiM) or molecular recognition feature (MoRF) reconciles many puzzling features of this motif and opens up new avenues for research.
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