Histone fold

The histone fold is a multifunctional domain. It is found in both histones and non-histone transcription factors. It serves a wide range of related functions including protein-DNA binding and protein dimerization.^[4] Non-histone examples include CBF/NF-Y, TBP-associated factors (TAFs), the TBP/TATA-binding negative cofactor 2 (NC2α/β), and the CHRAC15/CHRAC17 subunits of the nucleosome remodeling complex CHRAC.^[6]

The histone fold plays a crucial role in nucleosome formation by mediating interactions between histones. The largest interface surfaces are found in the heterotypic dimer interactions of H3-H4 and H2A-H2B. These interactions are primarily mediated by the "handshake" motif between histone fold domains. Additionally, the H2A structure has a unique loop modification at its interface, contributing to its distinct role in transcriptional activation.^{[citation needed]}

The nuclear transcription factor Y (NF-Y) also known as the CCAAT-binding factor (CBF) is a transcriptional factor highly conserved among eukaryotes (including humans). It is a heterotrimer composed of NFYA, NFYB, and NFYC. NFYA has a sequence-specific, non-histone-fold DNA-binding domain, while NFYB and NFYC both have a non-sequence-specific histone-fold DNA-binding domain. NFYB and NFYC form a structure similar to H2A/H2B.^[6]

The histone fold is thought to have evolved from ancestral peptide sets that formed helix-strand-helix motifs. These peptides are believed to have originated from ancient fragments, which may be precursors to the modern H3-H4 tetramer found in eukaryotes. Archaea possess single-chain histones with a similar DNA-packaging function, suggesting a shared ancestry between eukaryotes and archaea. One bacterium, Aquifex aeolicus, also has one archaeal-type histone gene from later horizontal gene transfer.^[2]

Expansion of bacterial genomic data has identified many other histone-fold proteins. The Bd0055 of Bdellovibrio bacteriovorus exhibits two unconventional (compared to eukaryotic and archaeal histone) modes of DNA-binding. The HLp of Leptospira perolatii is comparatively more conventional.^[7] Only 1.86% of bacteria genomes surveyed in 2023 contain a histone-fold protein, compared to 92.8% of genomes that encode HU (histone-like DNA-binding protein).^[8]