Institute for Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, , Magdeburg, Germany.
J R Soc Interface. 2013 Dec 4;11(91):20130971. doi: 10.1098/rsif.2013.0971. Print 2014 Feb 6.
Negative feedback control is a ubiquitous feature of biochemical systems, as is time delay between a signal and its response. Negative feedback in conjunction with time delay can lead to oscillations. In a cellular context, it might be beneficial to mitigate oscillatory behaviour to avoid recurring stress situations. This can be achieved by increasing the distance between the parameters of the system and certain thresholds, beyond which oscillations occur. This distance has been termed resistance. Here, we prove that in a generic three-dimensional negative feedback system the resistance of the system is modified by nested autoinhibitory feedbacks. Our system features negative feedbacks through both input-inhibition as well as output-activation, a signalling component with mass conservation and perfect adaptation. We show that these features render the system applicable to biological data, exemplified by the high osmolarity glycerol system in yeast and the mammalian p53 system. Output-activation is better supported by data than input-inhibition and also shows distinguished properties with respect to the system's stimulus. Our general approach might be useful in designing synthetic systems in which oscillations can be tuned by synthetic autoinhibitory feedbacks.
负反馈控制是生化系统的普遍特征,信号与其响应之间也存在时间延迟。负反馈与时间延迟相结合会导致振荡。在细胞环境中,减轻振荡行为以避免反复出现应激情况可能是有益的。这可以通过增加系统参数与某些阈值之间的距离来实现,超过该阈值就会发生振荡。这个距离被称为阻力。在这里,我们证明在一个通用的三维负反馈系统中,系统的阻力会受到嵌套自动抑制反馈的影响。我们的系统通过输入抑制和输出激活来实现负反馈,具有质量守恒和完美适应的信号成分。我们表明,这些特征使系统适用于生物数据,酵母中的高渗透压甘油系统和哺乳动物中的 p53 系统就是例证。输出激活比输入抑制更能得到数据的支持,并且相对于系统的刺激也表现出独特的特性。我们的一般方法可能有助于设计可以通过合成自动抑制反馈来调节振荡的合成系统。