Taylor histone sandbox

From Proteopedia

DNA is packaged into nucleosomes by wrapping around positively charged histone proteins. Histones are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation. Without histones, the unwound DNA in chromosomes would be very long; each human cell has about 1.8 meters of DNA, but wound on the histones it has about 90 micrometers (0.09 mm) of chromatin, which, when duplicated and condensed during mitosis, result in about 120 micrometers of chromosomes.^[1] DNA is wrapped around nucleosomes with approximately 50 base pairs of DNA between subsequent nucleosomes (also referred to as linker DNA). The assembled histones and DNA is called chromatin. During mitosis and meiosis, the condensed chromosomes are assembled through interactions between nucleosomes and other regulatory proteins.

Histone Structure

There are five major classes of histones: H1/H5, H2A, H2B, H3, and H4.^[2][3][4] Histones H2A, H2B, H3 and H4 are known as the core histones, while histones H1 and H5 are known as the linker histones.

The 4 'core' histones (H2A, H2B, H3 and H4) are relatively similar in structure and are highly conserved through evolution, all featuring a 'helix turn helix turn helix' motif (which allows the easy dimerisation). They also share the feature of long 'tails' on one end of the amino acid structure, which are often covalently modified to regulate gene expression.

Histone Quaternary Structure

Template:STRUCTURE 1aoi

The nucleosome core is formed of two H2A-H2B dimers and a H3-H4 tetramer, forming two nearly symmetrical halves by tertiary structure.^[5] 147 base pairs of DNA wrap around this core particle 1.65 times in a left-handed super-helical turn.^[5] The linker histone H1 binds the nucleosome and the entry and exit sites of the DNA, thus locking the DNA into place^[6] and allowing the formation of higher order structure.

In all, histones make five types of interactions with DNA:

• Helix-dipoles from alpha-helices in H2B, H3, and H4 cause a net positive charge to accumulate at the point of interaction with negatively charged phosphate groups on DNA
• Hydrogen bonds between the DNA backbone and the peptide bond in the backbone of histone proteins
• Interactions between the histone and deoxyribose sugars on DNA
• Salt bridges and hydrogen bonds between side chains of basic amino acids (especially lysine and arginine) and phosphate oxygens on DNA
• Non-specific minor groove insertions of the H3 and H2B N-terminal tails into two minor grooves each on the DNA molecule

In general, genes that are active have less bound histone, while inactive genes are highly associated with histones during interphase. It also appears that the structure of histones has been evolutionarily conserved, as any deleterious mutations would be severely maladaptive.

Chromatin regulation

Histones are subject to post translational modification by enzymes primarily on their N-terminal tails, but also in their globular domains. Such modifications include methylation, acetylation, phosphorylation, SUMOylation, ubiquitination, and ADP-ribosylation. This affects gene expression. The core of the histones H2A, H2B, and H3 can also be modified. Combinations of modifications are thought to constitute a code, the so-called "histone code".^[7][8] Histone modifications act in diverse biological processes such as gene regulation, DNA repair, chromosome condensation (in mitosis, spermatogenesis, and meiosis).^[9]

The common nomenclature of histone modifications is:

• The name of the histone (e.g., H3)
• The single-letter amino acid abbreviation (e.g., K for Lysine) and the amino acid position in the protein
• The type of modification (Me: methyl, P: phosphate, Ac: acetyl, Ub: ubiquitin)

So H3K4me1 denotes the monomethylation of the 4th residue (a lysine) from the start (i.e., the N-terminal) of the H3 protein.

History

Histones were discovered in 1884 by Albrecht Kossel. The word "histone" dates from the late 19th century and is from the German "Histon", of uncertain origin: perhaps from Greek histanai or from histos. Until the early 1990s, histones were dismissed by most as inert packing material for eukaryotic nuclear DNA, based in part on the "ball and stick" models of Mark Ptashne and others who believed that transcription was activated by protein-DNA and protein-protein interactions on largely naked DNA templates, as is the case in bacteria. During the 1980s, work by Michael Grunstein ^[10] demonstrated that eukaryotic histones repress gene transcription, and that the function of transcriptional activators is to overcome this repression. It is now known that histones play both positive and negative roles in gene expression, forming the basis of the histone code.

The discovery of the H5 histone appears to date back to 1970s,^[11][12] and in classification it has been grouped with H1.^[2][3][4]

See also

• Nucleosome
• Chromatin
• Histone-Modifying Enzymes
• Histone deacetylases
• Gene silencing
• Histone methyltransferase
• Histone acetyltransferase

References