The histone fold is a

structural motif In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have t ...

located near the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...

proteins, characterized by three

alpha helices An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

separated by two loops. This motif facilitates the formation of

heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

s, which subsequently assemble into a

histone octamer In molecular biology, a histone octamer is the eight-protein complex found at the center of a nucleosome core particle. It consists of two copies of each of the four core histone proteins ( H2A, H2B, H3, and H4). The octamer assembles when a ...

, playing a crucial role in the packaging of DNA into

nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone, histone proteins and resembles thread wrapped around a bobbin, spool. The nucleosome ...

s within

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...

. This fold is an ancient and highly conserved structural motif, essential for DNA compaction and regulation across a wide range of species.

Discovery

The histone fold motif was first discovered in

TATA box In molecular biology, the TATA box (also called the Goldberg–Hogness box) is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has a ...

-binding protein-associated factors, which play a key role in transcription.

Structure

The histone fold is typically around 70

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

long and is characterized by three

connected by two short, unstructured loops. In the absence of DNA, core histones assemble into head-to-tail intermediates. For instance, H3 and H4 first form heterodimers, which then combine to form a tetramer. Similarly, H2A and H2B form heterodimers. These interactions occur through hydrophobic "handshake" interactions between histone fold domains. Histones H4 and H2A can form internucleosomal contacts that, when acetylated, enable ionic interactions between peptides. These interactions can alter the surrounding internucleosomal contacts, leading to chromatin opening and increased accessibility for transcription.

Function

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.

Evolution

The histone fold is thought to have evolved from ancestral

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

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. Notably, archaeal single-chain histones, similar to eukaryotic histones, are found in the bacterium Aquifex aeolicus, suggesting a shared ancestry between eukaryotes and archaea, with possible lateral gene transfers to bacteria. Studies on species like

Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...

have revealed variations in the histone fold motif, particularly in the subunits of transcription initiation factors. These proteins contain histone-like structures, which show that the histone fold motif can also be found in non-histone proteins involved in protein-protein and protein-DNA interactions.

References

{{DEFAULTSORT:Histone Fold Protein folding Molecular biology Protein superfamilies