Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9722-7. doi: 10.1073/pnas.1221743110. Epub 2013 May 28.
Pirin is a nuclear nonheme Fe protein of unknown function present in all human tissues. Here we describe that pirin may act as a redox sensor for the nuclear factor κB (NF-κB) transcription factor, a critical mediator of intracellular signaling that has been linked to cellular responses to proinflammatory signals and controls the expression of a vast array of genes involved in immune and stress responses. Pirin's regulatory effect was tested with several metals and at different oxidations states, and our spectroscopic results show that only the ferric form of pirin substantially facilitates binding of NF-κB proteins to target κB genes, a finding that suggests that pirin performs a redox-sensing role in NF-κB regulation. The molecular mechanism of such a metal identity- and redox state-dependent regulation is revealed by our structural studies of pirin. The ferrous and ferric pirin proteins differ only by one electron, yet they have distinct conformations. The Fe center is shown to play an allosteric role on an R-shaped surface area that has two distinct conformations based on the identity and the formal redox state of the metal. We show that the R-shaped area composes the interface for pirin-NF-κB binding that is responsible for modulation of NF-κB's DNA-binding properties. The nonheme Fe protein pirin is proposed to serve as a reversible functional switch that enables NF-κB to respond to changes in the redox levels of the cell nucleus.
皮尔林是一种核非血红素 Fe 蛋白，其功能未知，存在于所有人体组织中。在这里，我们描述了皮尔林可能作为核因子 κB（NF-κB）转录因子的氧化还原传感器发挥作用，NF-κB 是一种细胞内信号转导的关键介质，与细胞对促炎信号的反应有关，并控制着参与免疫和应激反应的大量基因的表达。我们用几种金属和不同的氧化态测试了皮尔林的调节作用，我们的光谱结果表明，只有三价铁形式的皮尔林才能显著促进 NF-κB 蛋白与靶基因 κB 的结合，这一发现表明皮尔林在 NF-κB 调节中发挥氧化还原感应作用。我们对皮尔林的结构研究揭示了这种金属身份和氧化还原状态依赖性调节的分子机制。亚铁和三价皮尔林蛋白仅相差一个电子，但它们具有不同的构象。结果表明，Fe 中心在 R 形表面上发挥变构作用，该表面基于金属的身份和形式氧化还原状态具有两种不同的构象。我们表明，R 形区域构成了皮尔林-NF-κB 结合的界面，负责调节 NF-κB 的 DNA 结合特性。提议非血红素 Fe 蛋白皮尔林作为一种可逆的功能开关，使 NF-κB 能够响应细胞核氧化还原水平的变化。
