The Rel Homology region/domain (RHR or RHD) is an N-terminal DNA-binding domain that is found in a family of eukaryotic transcription factors, which includes NF-κB, Dorsal, Relish, NFAT, among others. The NF-κB and Rel proteins can readily form homodimers and heterodimers to bind to DNA and activate transcription. Nevertheless, their sequences and structures make it clear that the NF-κB and Rel proteins are members of distinct subfamilies[1].
The NF-κB transcription factors include Relish (in insects) and p50/p105 (aka NF-κB1) and p52/p100 (aka NF-κB2) (in vertebrates). NF-κB proteins contain an N-terminal RHD and C-terminal sequences that consist primarily of multiple copies of 33-amino acid ankyrin (ANK) repeats that bind to the RHD and inhibit its DNA-binding activity.
Rel family proteins include Dorsal, Dif, c-Rel, RelA, and RelB. Like NF-κB proteins, the Rel proteins have an N-terminal RHD, but their C-terminal sequences contain transcriptional activation domains and no ANK repeats. Thus, Rel proteins do not need to be processed to shorter forms to be active.
In NFAT proteins, the RHD is centrally located and is bounded by longer N- and C-terminal domains. In human and mouse, the NFAT family includes five members: NFAT1-5. All NFAT proteins except NFAT5 are regulated by calcium signaling and contain sequences that act as binding sites for the protein phosphatase calcineurin, which is required for induced nuclear localization of NFAT proteins 1-4. Unlike the other NFAT proteins, NFAT5 (aka TonEBP) does not bind to calcineurin, is activated by osmotic stress, can form homodimers in solution, and is generally constitutively located in the nucleus[2].