Marciano David C, Lua Rhonald C, Katsonis Panagiotis, Amin Shivas R, Herman Christophe, Lichtarge Olivier
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2014 Jun 26;7(6):1789-95. doi: 10.1016/j.celrep.2014.05.018. Epub 2014 Jun 5.
Natural selection for specific functions places limits upon the amino acid substitutions a protein can accept. Mechanisms that expand the range of tolerable amino acid substitutions include chaperones that can rescue destabilized proteins and additional stability-enhancing substitutions. Here, we present an alternative mechanism that is simple and uses a frequently encountered network motif. Computational and experimental evidence shows that the self-correcting, negative-feedback gene regulation motif increases repressor expression in response to deleterious mutations and thereby precisely restores repression of a target gene. Furthermore, this ability to rescue repressor function is observable across the Eubacteria kingdom through the greater accumulation of amino acid substitutions in negative-feedback transcription factors compared to genes they control. We propose that negative feedback represents a self-contained genetic canalization mechanism that preserves phenotype while permitting access to a wider range of functional genotypes.
针对特定功能的自然选择对蛋白质所能接受的氨基酸替换施加了限制。扩展可耐受氨基酸替换范围的机制包括能够拯救不稳定蛋白质的伴侣蛋白以及其他增强稳定性的替换。在此，我们提出一种简单的替代机制，该机制利用了一种常见的网络基序。计算和实验证据表明，自我校正的负反馈基因调控基序会响应有害突变增加阻遏物表达，从而精确恢复对靶基因的抑制。此外，通过与它们所控制的基因相比，负反馈转录因子中氨基酸替换的更多积累，这种拯救阻遏物功能的能力在整个真细菌界都可观察到。我们提出，负反馈代表一种自成体系的遗传稳态机制，它在允许获得更广泛功能基因型的同时保持表型。
