Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
NMR Research Centre, Indian Institute of Science, Bangalore, Karnataka 560012, India.
Biochemistry. 2021 Feb 23;60(7):513-523. doi: 10.1021/acs.biochem.0c00837. Epub 2021 Feb 8.
The NF-κB family of transcription factors is a key regulator of the immune response in the vertebrates. The family comprises five proteins that function as dimers formed in various combinations among the members, with the RelA-p50 dimer being physiologically the most abundant. While most of the 15 possible dimers are scarcely present in the cell with some remaining experimentally undetected to date, there are specific gene sets that are only activated by certain sparsely populated NF-κB dimers. The mechanism of transcription activation of such specific genes that are activated only by specific NF-κB dimers remains unclear. Here we show that the dimer interfacial residues control the stabilization of the global hydrogen bond network of the NF-κB dimerization domain, which, in turn, controls the thermodynamic stabilization of different NF-κB dimers. The relatively low thermodynamic stability of the RelA-RelA homodimer is critical as it facilitates the formation of the more stable RelA-p50 heterodimer. Through the modulation of the thermodynamic stability of the RelA-RelA homodimer, the kinetics of the RelA-p50 heterodimer formation can be regulated. This phenomenon provides an insight into the mechanism of RelA-RelA specific target gene regulation in physiology.
NF-κB 转录因子家族是脊椎动物免疫反应的关键调节剂。该家族由五个蛋白组成，它们以成员之间的各种组合形成二聚体，其中 RelA-p50 二聚体在生理上最为丰富。虽然大多数 15 种可能的二聚体在细胞中很少存在，有些至今仍在实验上未被检测到，但有特定的基因集仅被某些稀疏存在的 NF-κB 二聚体激活。仅由特定 NF-κB 二聚体激活的特定基因的转录激活机制尚不清楚。在这里，我们表明二聚体界面残基控制 NF-κB 二聚化结构域的整体氢键网络的稳定，进而控制不同 NF-κB 二聚体的热力学稳定性。RelA-RelA 同源二聚体的热力学稳定性相对较低是至关重要的，因为它促进了更稳定的 RelA-p50 异源二聚体的形成。通过调节 RelA-RelA 同源二聚体的热力学稳定性，可以调节 RelA-p50 异源二聚体形成的动力学。这种现象为生理条件下 RelA-RelA 特定靶基因调控的机制提供了深入了解。
