Hinds M G, Smits C, Fredericks-Short R, Risk J M, Bailey M, Huang D C S, Day C L
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Cell Death Differ. 2007 Jan;14(1):128-36. doi: 10.1038/sj.cdd.4401934. Epub 2006 Apr 28.
All BH3-only proteins, key initiators of programmed cell death, interact tightly with multiple binding partners and have sequences of low complexity, properties that are the hallmark of intrinsically unstructured proteins (IUPs). We show, using spectroscopic methods, that the BH3-only proteins Bim, Bad and Bmf are unstructured in the absence of binding partners. Detailed sequence analyses are consistent with this observation and suggest that most BH3-only proteins are unstructured. When Bim binds and inactivates prosurvival proteins, most residues remain disordered, only the BH3 element becomes structured, and the short alpha-helical molecular recognition element can be considered to behave as a 'bead on a string'. Coupled folding and binding is typical of many IUPs that have important signaling roles, such as BH3-only proteins, as the inherent structural plasticity favors interaction with multiple targets. This understanding offers promise for the development of BH3 mimetics, as multiple modes of binding are tolerated.
所有仅含BH3结构域的蛋白都是程序性细胞死亡的关键启动因子，它们与多个结合伴侣紧密相互作用，并且具有低复杂性序列，这些特性是内在无序蛋白（IUPs）的标志。我们使用光谱方法表明，在没有结合伴侣的情况下，仅含BH3结构域的蛋白Bim、Bad和Bmf是无序的。详细的序列分析与这一观察结果一致，并表明大多数仅含BH3结构域的蛋白是无序的。当Bim结合并使促生存蛋白失活时，大多数残基仍然无序，只有BH3元件变得有序，并且短的α-螺旋分子识别元件可以被认为表现为“绳上之珠”。耦合折叠和结合是许多具有重要信号传导作用的IUPs的典型特征，例如仅含BH3结构域的蛋白，因为固有的结构可塑性有利于与多个靶点相互作用。这种理解为BH3模拟物的开发带来了希望，因为可以容忍多种结合模式。
