Effects of sequestration on signal transduction cascades
Effects of sequestration on signal transduction cascades
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DOI：
10.1111/j.1742-4658.2006.05105.x
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发表时间：
2006-03-01
期刊：
影响因子：
5.4
通讯作者：
Kholodenko, BN
中科院分区：
文献类型：
--
作者：
Blüthgen, N;Bruggeman, FJ;Kholodenko, BN
大多数信号转导途径的构件是通过共价修饰来控制蛋白质靶标的活性的酶，例如激酶和磷酸酶。以前已显示[Goldbeter A＆Koshland DE（1981）Proc Natl Acad Sci USA78，6840-6844]，如果它们的催化酶与靶蛋白底物饱和，则这些系统可能会对刺激的变化高度敏感。该机制称为零级超敏，可能会设定阈值，从而滤除子阈值刺激。关于蛋白质丰度的实验数据表明，酶及其靶蛋白以相当的浓度存在。在这些条件下，可以通过酶隔离靶蛋白的很大一部分。这会导致超敏性降低，因此在大多数体内信号级联反应中所存在的条件下，提出的机制不可能考虑到超敏性。此外，我们表明隔离改变了共价修改周期的动力学，并可能解释了信号终止和符号敏感的延迟。最后，我们分析了隔离对复杂信号转导级联动力学的影响：有丝分裂原激活的蛋白激酶（MAPK）级联反馈的影响。我们表明，隔离限制了该级联反应中的超敏性，从而消除了负反馈引起的振荡潜力。
The building blocks of most signal transduction pathways are pairs of enzymes, such as kinases and phosphatases, that control the activity of protein targets by covalent modification. It has previously been shown [Goldbeter A & Koshland DE (1981) Proc Natl Acad Sci USA78, 6840-6844] that these systems can be highly sensitive to changes in stimuli if their catalysing enzymes are saturated with their target protein substrates. This mechanism, termed zero-order ultrasensitivity, may set thresholds that filter out subthreshold stimuli. Experimental data on protein abundance suggest that the enzymes and their target proteins are present in comparable concentrations. Under these conditions a large fraction of the target protein may be sequestrated by the enzymes. This causes a reduction in ultrasensitivity so that the proposed mechanism is unlikely to account for ultrasensitivity under the conditions present in most in vivo signalling cascades. Furthermore, we show that sequestration changes the dynamics of a covalent modification cycle and may account for signal termination and a sign-sensitive delay. Finally, we analyse the effect of sequestration on the dynamics of a complex signal transduction cascade: the mitogen-activated protein kinase (MAPK) cascade with negative feedback. We show that sequestration limits ultrasensitivity in this cascade and may thereby abolish the potential for oscillations induced by negative feedback.