posted on 2021-02-08, 16:44authored byManish Kumar, Nitin Dhaka, Tahseen Raza, Prikshat Dadhwal, Hanudatta S. Atreya, Sulakshana P. Mukherjee
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.