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34  structures 1401  species 0  interactions 9442  sequences 161  architectures

Family: Linker_histone (PF00538)

Summary: linker histone H1 and H5 family

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This is the Wikipedia entry entitled "Histone". More...

Histone Edit Wikipedia article

Schematic representation of the assembly of the core histones into the nucleosome.

In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes.[1][2] They are the chief protein components of chromatin, acting as spools around which DNA winds, and playing a role in gene regulation. Without histones, the unwound DNA in chromosomes would be very long (a length to width ratio of more than 10 million to 1 in human DNA). For example, each human diploid cell (containing 23 pairs of chromosomes) has about 1.8 meters of DNA; wound on the histones, the diploid cell has about 90 micrometers (0.09 mm) of chromatin. When the diploid cells are duplicated and condensed during mitosis, the result is about 120 micrometers of chromosomes.[3]

Core histone H2A/H2B/H3/H4
Protein H2AFJ PDB 1aoi.png
PDB rendering of Complex between nucleosome core particle (h3,h4,h2a,h2b) and 146 bp long DNA fragment based on 1aoi.
Pfam clanCL0012
linker histone H1 and H5 family
PBB Protein HIST1H1B image.jpg
PDB rendering of HIST1H1B based on 1ghc.

Classes and histone variants

Five major families of histones exist: H1/H5, H2A, H2B, H3, and H4.[2][4][5][6] Histones H2A, H2B, H3 and H4 are known as the core histones, while histones H1/H5 are known as the linker histones.

The core histones all exist as dimers, which are similar in that they all possess the histone fold domain: three alpha helices linked by two loops. It is this helical structure that allows for interaction between distinct dimers, particularly in a head-tail fashion (also called the handshake motif).[7] The resulting four distinct dimers then come together to form one octameric nucleosome core, approximately 63 Angstroms in diameter (a solenoid (DNA)-like particle). Around 146 base pairs (bp) of DNA wrap around this core particle 1.65 times in a left-handed super-helical turn to give a particle of around 100 Angstroms across.[8] The linker histone H1 binds the nucleosome at the entry and exit sites of the DNA, thus locking the DNA into place[9] and allowing the formation of higher order structure. The most basic such formation is the 10 nm fiber or beads on a string conformation. This involves the wrapping of DNA around nucleosomes with approximately 50 base pairs of DNA separating each pair of nucleosomes (also referred to as linker DNA). Higher-order structures include the 30 nm fiber (forming an irregular zigzag) and 100 nm fiber, these being the structures found in normal cells. During mitosis and meiosis, the condensed chromosomes are assembled through interactions between nucleosomes and other regulatory proteins.

Histones are subdivided into canonical replication-dependent histones that are expressed during the S-phase of cell cycle and replication-independent histone variants, expressed during the whole cell cycle. In animals, genes encoding canonical histones are typically clustered along the chromosome, lack introns and use a stem loop structure at the 3’ end instead of a polyA tail. Genes encoding histone variants are usually not clustered, have introns and their mRNAs are regulated with polyA tails. Complex multicellular organisms typically have a higher number of histone variants providing a variety of different functions. Recent data are accumulating about the roles of diverse histone variants highlighting the functional links between variants and the delicate regulation of organism development. Histone variants from different organisms, their classification and variant specific features can be found in "HistoneDB 2.0 - Variants" database.

The following is a list of human histone proteins:

Super family Family Subfamily Members
Linker H1 H1F H1F0, H1FNT, H1FOO, H1FX


The nucleosome core is formed of two H2A-H2B dimers and a H3-H4 tetramer, forming two nearly symmetrical halves by tertiary structure (C2 symmetry; one macromolecule is the mirror image of the other).[8] The H2A-H2B dimers and H3-H4 tetramer also show pseudodyad symmetry. 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 (DNA-binding protein motif that recognize specific DNA sequence). They also share the feature of long 'tails' on one end of the amino acid structure - this being the location of post-translational modification (see below).[10]

Archaeal histone only contains a H3-H4 like dimeric structure made out of the same protein. Such dimeric structures can stack into a tall superhelix ("supernucleosome") onto which DNA coils in a manner similar to nucleosome spools.[11] Only some archaeal histones have tails.[12]

It has been proposed that histone proteins are evolutionarily related to the helical part of the extended AAA+ ATPase domain, the C-domain, and to the N-terminal substrate recognition domain of Clp/Hsp100 proteins. Despite the differences in their topology, these three folds share a homologous helix-strand-helix (HSH) motif.[10]

Using an electron paramagnetic resonance spin-labeling technique, British researchers measured the distances between the spools around which eukaryotic cells wind their DNA. They determined the spacings range from 59 to 70 Ã….[13]

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

  • Helix-dipoles form alpha-helixes 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 amide group on the main chain of histone proteins
  • Nonpolar 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

The highly basic nature of histones, aside from facilitating DNA-histone interactions, contributes to their water solubility.

Histones are subject to post translational modification by enzymes primarily on their N-terminal tails, but also in their globular domains.[14][15] Such modifications include methylation, citrullination, acetylation, phosphorylation, SUMOylation, ubiquitination, and ADP-ribosylation. This affects their function of gene regulation.

In general, genes that are active have less bound histone, while inactive genes are highly associated with histones during interphase.[16] It also appears that the structure of histones has been evolutionarily conserved, as any deleterious mutations would be severely maladaptive. All histones have a highly positively charged N-terminus with many lysine and arginine residues.


Histones were discovered in 1884 by Albrecht Kossel.[17] The word "histone" dates from the late 19th century and is derived from the German word "Histon", a word itself of uncertain origin - perhaps from the Greek histanai or histos.

In the early 1960s, before the types of histones were known and before histones were known to be highly conserved across taxonomically diverse organisms, James F. Bonner and his collaborators began a study of these proteins that were known to be tightly associated with the DNA in the nucleus of higher organisms.[18] Bonner and his postdoctoral fellow Ru Chih C. Huang showed that isolated chromatin would not support RNA transcription in the test tube, but if the histones were extracted from the chromatin, RNA could be transcribed from the remaining DNA.[19] Their paper became a citation classic.[20] Paul T'so and James Bonner had called together a World Congress on Histone Chemistry and Biology in 1964, in which it became clear that there was no consensus on the number of kinds of histone and that no one knew how they would compare when isolated from different organisms.[21][18] Bonner and his collaborators then developed methods to separate each type of histone, purified individual histones, compared amino acid compositions in the same histone from different organisms, and compared amino acid sequences  of the same histone from different organisms in collaboration with Emil Smith from UCLA.[22] For example, they found Histone IV sequence to be highly conserved between peas and calf thymus.[22] However, their work on the biochemical characteristics of individual histones did not reveal how the histones interacted with each other or with DNA to which they were tightly bound.[21]

Also in the 1960s, Vincent Allfrey and Alfred Mirsky had suggested, based on their analyses of histones, that acetylation and methylation of histones could provide a transcriptional control mechanism, but did not have available the kind of detailed analysis that later investigators were able to conduct to show how such regulation could be gene-specific.[23] Until the early 1990s, histones were dismissed by most as inert packing material for eukaryotic nuclear DNA, a view based in part on the 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, Yahli Lorch and Roger Kornberg[24] showed that a nucleosome on a core promoter prevents the initiation of transcription in vitro, and Michael Grunstein[25] demonstrated that histones repress transcription in vivo, leading to the idea of the nucleosome as a general gene repressor. Relief from repression is believed to involve both histone modification and the action of chromatin-remodeling complexes. Vincent Allfrey and Alfred Mirsky had earlier proposed a role of histone modification in transcriptional activation,[26] regarded as a molecular manifestation of epigenetics. Michael Grunstein[27] and David Allis[28] found support for this proposal, in the importance of histone acetylation for transcription in yeast and the activity of the transcriptional activator Gcn5 as a histone acetyltransferase.

The discovery of the H5 histone appears to date back to the 1970s,[29] and it is now considered an isoform of Histone H1.[2][4][5][6]

Conservation across species

Histones are found in the nuclei of eukaryotic cells, and in certain Archaea, namely Proteoarchaea and Euryarchaea, but not in bacteria.[12] The unicellular algae known as dinoflagellates were previously thought to be the only eukaryotes that completely lack histones,[30] however, later studies showed that their DNA still encodes histone genes.[31] Unlike the core histones, lysine-rich linker histone (H1) proteins are found in bacteria, otherwise known as nucleoprotein HC1/HC2.[32]

Archaeal histones may well resemble the evolutionary precursors to eukaryotic histones.[12] Histone proteins are among the most highly conserved proteins in eukaryotes, emphasizing their important role in the biology of the nucleus.[2]:939 In contrast mature sperm cells largely use protamines to package their genomic DNA, most likely because this allows them to achieve an even higher packaging ratio.[33]

There are some variant forms in some of the major classes. They share amino acid sequence homology and core structural similarity to a specific class of major histones but also have their own feature that is distinct from the major histones. These minor histones usually carry out specific functions of the chromatin metabolism. For example, histone H3-like CENPA is associated with only the centromere region of the chromosome. Histone H2A variant H2A.Z is associated with the promoters of actively transcribed genes and also involved in the prevention of the spread of silent heterochromatin.[34] Furthermore, H2A.Z has roles in chromatin for genome stability.[35] Another H2A variant H2A.X is phosphorylated at S139 in regions around double-strand breaks and marks the region undergoing DNA repair.[36] Histone H3.3 is associated with the body of actively transcribed genes.[37]

Evolutionary origin

Histones are believed to have evolved from ribosomal proteins with which they share much in common, both being short and basic proteins. [38]


Compacting DNA strands

Histones act as spools around which DNA winds. This enables the compaction necessary to fit the large genomes of eukaryotes inside cell nuclei: the compacted molecule is 40,000 times shorter than an unpacked molecule.

Chromatin regulation

Histones undergo posttranslational modifications that alter their interaction with DNA and nuclear proteins. The H3 and H4 histones have long tails protruding from the nucleosome, which can be covalently modified at several places. Modifications of the tail include methylation, acetylation, phosphorylation, ubiquitination, SUMOylation, citrullination, and ADP-ribosylation. The core of the histones H2A and H2B can also be modified. Combinations of modifications are thought to constitute a code, the so-called "histone code".[39][40] Histone modifications act in diverse biological processes such as gene regulation, DNA repair, chromosome condensation (mitosis) and spermatogenesis (meiosis).[41]

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)
  • The number of modifications (only Me is known to occur in more than one copy per residue. 1, 2 or 3 is mono-, di- or tri-methylation)

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

Examples of histone modifications in transcriptional regulation
Type of
H3K4 H3K9 H3K14 H3K27 H3K79 H3K36 H4K20 H2BK5 H2BK20
mono-methylation activation[42] activation[43] activation[43] activation[43][44] activation[43] activation[43]
di-methylation repression[45] repression[45] activation[44]
tri-methylation activation[46] repression[43] repression[43] activation,[44]
activation repression[45]
acetylation activation[47] activation[46] activation[46] activation[48] activation

Functions of histone modifications

Schematic representation of histone modifications. Based on Rodriguez-Paredes and Esteller, Nature, 2011

A huge catalogue of histone modifications have been described, but a functional understanding of most is still lacking. Collectively, it is thought that histone modifications may underlie a histone code, whereby combinations of histone modifications have specific meanings. However, most functional data concerns individual prominent histone modifications that are biochemically amenable to detailed study.

Chemistry of histone modifications

Lysine methylation

Methyl lysine.svg

The addition of one, two, or many methyl groups to lysine has little effect on the chemistry of the histone; methylation leaves the charge of the lysine intact and adds a minimal number of atoms so steric interactions are mostly unaffected. However, proteins containing Tudor, chromo or PHD domains, amongst others, can recognise lysine methylation with exquisite sensitivity and differentiate mono, di and tri-methyl lysine, to the extent that, for some lysines (e.g.: H4K20) mono, di and tri-methylation appear to have different meanings. Because of this, lysine methylation tends to be a very informative mark and dominates the known histone modification functions.

Glutamine serotonylation

Recently it has been shown, that the addition of a serotonin group to the position 5 glutamine of H3, happens in serotonergic cells such as neurons. This is part of the differentiation of the serotonergic cells. This post-translational modification happens in conjunction with the H3K4me3 modification. The serotonylation potentiates the binding of the general transcription factor TFIID to the TATA box.[49]

Arginine methylation

Methyl arginine.svg

What was said above of the chemistry of lysine methylation also applies to arginine methylation, and some protein domains—e.g., Tudor domains—can be specific for methyl arginine instead of methyl lysine. Arginine is known to be mono- or di-methylated, and methylation can be symmetric or asymmetric, potentially with different meanings.

Arginine citrullination

Enzymes called peptidylarginine deiminases (PADs) hydrolyze the imine group of arginines and attach a keto group, so that there is one less positive charge on the amino acid residue. This process has been involved in the activation of gene expression by making the modified histones less tightly bound to DNA and thus making the chromatin more accessible.[50] PADs can also produce the opposite effect by removing or inhibiting mono-methylation of arginine residues on histones and thus antagonizing the positive effect arginine methylation has on transcriptional activity.[51]

Lysine acetylation

Acetyl lysine.tif

Addition of an acetyl group has a major chemical effect on lysine as it neutralises the positive charge. This reduces electrostatic attraction between the histone and the negatively charged DNA backbone, loosening the chromatin structure; highly acetylated histones form more accessible chromatin and tend to be associated with active transcription. Lysine acetylation appears to be less precise in meaning than methylation, in that histone acetyltransferases tend to act on more than one lysine; presumably this reflects the need to alter multiple lysines to have a significant effect on chromatin structure. The modification includes H3K27ac.

Serine/threonine/tyrosine phosphorylation

Amino acid phosphorylations.tif

Addition of a negatively charged phosphate group can lead to major changes in protein structure, leading to the well-characterised role of phosphorylation in controlling protein function. It is not clear what structural implications histone phosphorylation has, but histone phosphorylation has clear functions as a post-translational modification, and binding domains such as BRCT have been characterised.

Functions in transcription

Most well-studied histone modifications are involved in control of transcription.

Actively transcribed genes

Two histone modifications are particularly associated with active transcription:

Trimethylation of H3 lysine 4 (H3K4me3)
This trimethylation occurs at the promoter of active genes[52][53][54] and is performed by the COMPASS complex.[55][56][57] Despite the conservation of this complex and histone modification from yeast to mammals, it is not entirely clear what role this modification plays. However, it is an excellent mark of active promoters and the level of this histone modification at a gene's promoter is broadly correlated with transcriptional activity of the gene. The formation of this mark is tied to transcription in a rather convoluted manner: early in transcription of a gene, RNA polymerase II undergoes a switch from initiating’ to ‘elongating’, marked by a change in the phosphorylation states of the RNA polymerase II C terminal domain (CTD). The same enzyme that phosphorylates the CTD also phosphorylates the Rad6 complex,[58][59] which in turn adds a ubiquitin mark to H2B K123 (K120 in mammals).[60] H2BK123Ub occurs throughout transcribed regions, but this mark is required for COMPASS to trimethylate H3K4 at promoters.[61][62]
Trimethylation of H3 lysine 36 (H3K36me3)
This trimethylation occurs in the body of active genes and is deposited by the methyltransferase Set2.[63] This protein associates with elongating RNA polymerase II, and H3K36Me3 is indicative of actively transcribed genes.[64] H3K36Me3 is recognised by the Rpd3 histone deacetylase complex, which removes acetyl modifications from surrounding histones, increasing chromatin compaction and repressing spurious transcription.[65][66][67] Increased chromatin compaction prevents transcription factors from accessing DNA, and reduces the likelihood of new transcription events being initiated within the body of the gene. This process therefore helps ensure that transcription is not interrupted.

Repressed genes

Three histone modifications are particularly associated with repressed genes:

Trimethylation of H3 lysine 27 (H3K27me3)
This histone modification is depositied by the polycomb complex PRC2.[68] It is a clear marker of gene repression,[69] and is likely bound by other proteins to exert a repressive function. Another polycomb complex, PRC1, can bind H3K27me3[69] and adds the histone modification H2AK119Ub which aids chromatin compaction.[70][71] Based on this data it appears that PRC1 is recruited through the action of PRC2, however, recent studies show that PRC1 is recruited to the same sites in the absence of PRC2.[72][73]
Di and tri-methylation of H3 lysine 9 (H3K9me2/3)
H3K9me2/3 is a well-characterised marker for heterochromatin, and is therefore strongly associated with gene repression. The formation of heterochromatin has been best studied in the yeast Schizosaccharomyces pombe, where it is initiated by recruitment of the RNA-induced transcriptional silencing (RITS) complex to double stranded RNAs produced from centromeric repeats.[74] RITS recruits the Clr4 histone methyltransferase which deposits H3K9me2/3.[75] This process is called histone methylation. H3K9Me2/3 serves as a binding site for the recruitment of Swi6 (heterochromatin protein 1 or HP1, another classic heterochromatin marker)[76][77] which in turn recruits further repressive activities including histone modifiers such as histone deacetylases and histone methyltransferases.[78]
Trimethylation of H4 lysine 20 (H4K20me3)
This modification is tightly associated with heterochromatin,[79][80] although its functional importance remains unclear. This mark is placed by the Suv4-20h methyltransferase, which is at least in part recruited by heterochromatin protein 1.[79]

Bivalent promoters

Analysis of histone modifications in embryonic stem cells (and other stem cells) revealed many gene promoters carrying both H3K4Me3 and H3K27Me3, in other words these promoters display both activating and repressing marks simultaneously. This peculiar combination of modifications marks genes that are poised for transcription; they are not required in stem cells, but are rapidly required after differentiation into some lineages. Once the cell starts to differentiate, these bivalent promoters are resolved to either active or repressive states depending on the chosen lineage.[81]

Other functions

DNA damage

Marking sites of DNA damage is an important function for histone modifications. It also protects DNA from getting destroyed by ultraviolet radiation of sun.

Phosphorylation of H2AX at serine 139 (γH2AX)
Phosphorylated H2AX (also known as gamma H2AX) is a marker for DNA double strand breaks,[82] and forms part of the response to DNA damage.[36][83] H2AX is phosphorylated early after detection of DNA double strand break, and forms a domain extending many kilobases either side of the damage.[82][84][85] Gamma H2AX acts as a binding site for the protein MDC1, which in turn recruits key DNA repair proteins[86] (this complex topic is well reviewed in[87]) and as such, gamma H2AX forms a vital part of the machinery that ensures genome stability.
Acetylation of H3 lysine 56 (H3K56Ac)
H3K56Acx is required for genome stability.[88][89] H3K56 is acetylated by the p300/Rtt109 complex,[90][91][92] but is rapidly deacetylated around sites of DNA damage. H3K56 acetylation is also required to stabilise stalled replication forks, preventing dangerous replication fork collapses.[93][94] Although in general mammals make far greater use of histone modifications than microorganisms, a major role of H3K56Ac in DNA replication exists only in fungi, and this has become a target for antibiotic development.[95]

DNA repair

Trimethylation of H3 lysine 36 (H3K36me3)

H3K36me3 has the ability to recruit the MSH2-MSH6 (hMutSα) complex of the DNA mismatch repair pathway.[96] Consistently, regions of the human genome with high levels of H3K36me3 accumulate less somatic mutations due to mismatch repair activity.[97]

Chromosome condensation

Phosphorylation of H3 at serine 10 (phospho-H3S10)
The mitotic kinase aurora B phosphorylates histone H3 at serine 10, triggering a cascade of changes that mediate mitotic chromosome condensation.[98][99] Condensed chromosomes therefore stain very strongly for this mark, but H3S10 phosphorylation is also present at certain chromosome sites outside mitosis, for example in pericentric heterochromatin of cells during G2. H3S10 phosphorylation has also been linked to DNA damage caused by R-loop formation at highly transcribed sites.[100]
Phosphorylation H2B at serine 10/14 (phospho-H2BS10/14)
Phosphorylation of H2B at serine 10 (yeast) or serine 14 (mammals) is also linked to chromatin condensation, but for the very different purpose of mediating chromosome condensation during apoptosis.[101][102] This mark is not simply a late acting bystander in apoptosis as yeast carrying mutations of this residue are resistant to hydrogen peroxide-induced apoptotic cell death.


Epigenetic modifications of histone tails in specific regions of the brain are of central importance in addictions.[103][104][105] Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions.[103]

Cigarette smokers (about 15% of the US population) are usually addicted to nicotine.[106] After 7 days of nicotine treatment of mice, acetylation of both histone H3 and histone H4 was increased at the FosB promoter in the nucleus accumbens of the brain, causing 61% increase in FosB expression.[107] This would also increase expression of the splice variant Delta FosB. In the nucleus accumbens of the brain, Delta FosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.[108][109]

About 7% of the US population is addicted to alcohol. In rats exposed to alcohol for up to 5 days, there was an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain amygdala complex. This acetylation is an activating mark for pronociceptin. The nociceptin/nociceptin opioid receptor system is involved in the reinforcing or conditioning effects of alcohol.[110]

Methamphetamine addiction occurs in about 0.2% of the US population.[111] Chronic methamphetamine use causes methylation of the lysine in position 4 of histone 3 located at the promoters of the c-fos and the C-C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens (NAc).[112] c-fos is well known to be important in addiction.[113] The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.[112]

Histone synthesis

The first step of chromatin structure duplication is the synthesis of histone proteins: H1, H2A, H2B, H3, H4. These proteins are synthesized during S phase of the cell cycle. There are different mechanisms which contribute to the increase of histone synthesis.


Yeast carry one or two copies of each histone gene, which are not clustered but rather scattered throughout chromosomes. Histone gene transcription is controlled by multiple gene regulatory proteins such as transcription factors which bind to histone promoter regions. In budding yeast, the candidate gene for activation of histone gene expression is SBF. SBF is a transcription factor that is activated in late G1 phase, when it dissociates from its repressor Whi5. This occurs when Whi5 is phosphorylated by Cdc8 which is a G1/S Cdk.[114] Suppression of histone gene expression outside of S phases is dependent on Hir proteins which form inactive chromatin structure at the locus of histone genes, causing transcriptional activators to be blocked.[115][116]


In metazoans the increase in the rate of histone synthesis is due to the increase in processing of pre-mRNA to its mature form as well as decrease in mRNA degradation; this results in an increase of active mRNA for translation of histone proteins. The mechanism for mRNA activation has been found to be the removal of a segment of the 3’ end of the mRNA strand, and is dependent on association with stem-loop binding protein (SLBP).[117] SLBP also stabilizes histone mRNAs during S phase by blocking degradation by the 3’hExo nuclease.[118] SLBP levels are controlled by cell-cycle proteins, causing SLBP to accumulate as cells enter S phase and degrade as cells leave S phase. SLBP are marked for degradation by phosphorylation at two threonine residues by cyclin dependent kinases, possibly cyclin A/ cdk2, at the end of S phase.[119] Metazoans also have multiple copies of histone genes clustered on chromosomes which are localized in structures called Cajal bodies as determined by genome-wide chromosome conformation capture analysis (4C-Seq).[120]

Link between cell-cycle control machinery and histone synthesis

Nuclear protein Ataxia-Telangiectasia (NPAT), also known as nuclear protein coactivator of histone transcription, is a transcription factor which activates histone gene transcription on chromosomes 1 and 6 of human cells. NPAT is also a substrate of cyclin E-Cdk2, which is required for the transition between G1 phase and S phase. NPAT activates histone gene expression only after it has been phosphorylated by the G1/S-Cdk cyclin E-Cdk2 in early S phase.[121] This shows an important regulatory link between cell-cycle control and histone synthesis.

See also


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External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Histone H1". More...

Histone H1 Edit Wikipedia article

linker histone H1 and H5 family
PBB Protein HIST1H1B image.jpg
PDB rendering of HIST1H1B based on 1ghc.

Histone H1 is one of the five main histone protein families which are components of chromatin in eukaryotic cells. Though highly conserved, it is nevertheless the most variable histone in sequence across species.


A diagram showing where H1 can be found in the nucleosome

Metazoan H1 proteins feature a central globular "winged helix" domain and long C- and short N-terminal tails. H1 is involved with the packing of the "beads on a string" sub-structures into a high order structure, whose details have not yet been solved.[1] H1 found in protists and bacteria, otherwise known as nucleoprotein HC1/HC2, lack the central domain and the N-terminal tail.[2]

H1 is less conserved than core histones. The globular domain is the most conserved part of H1.[3]


Unlike the other histones, H1 does not make up the nucleosome "bead". Instead, it sits on top of the structure, keeping in place the DNA that has wrapped around the nucleosome. H1 is present in half the amount of the other four histones, which contribute two molecules to each nucleosome bead. In addition to binding to the nucleosome, the H1 protein binds to the "linker DNA" (approximately 20-80 nucleotides in length) region between nucleosomes, helping stabilize the zig-zagged 30 nm chromatin fiber.[4] Much has been learned about histone H1 from studies on purified chromatin fibers. Ionic extraction of linker histones from native or reconstituted chromatin promotes its unfolding under hypotonic conditions from fibers of 30 nm width to beads-on-a-string nucleosome arrays.[5][6][7]

It is uncertain whether H1 promotes a solenoid-like chromatin fiber, in which exposed linker DNA is shortened, or whether it merely promotes a change in the angle of adjacent nucleosomes, without affecting linker length[8] However, linker histones have been demonstrated to drive the compaction of chromatin fibres that had been reconstituted in vitro using synthetic DNA arrays of the strong '601' nucleosome positioning element.[9] Nuclease digestion and DNA footprinting experiments suggest that the globular domain of histone H1 localizes near the nucleosome dyad, where it protects approximately 15-30 base pairs of additional DNA.[10][11][12][13] In addition, experiments on reconstituted chromatin reveal a characteristic stem motif at the dyad in the presence of H1.[14] Despite gaps in our understanding, a general model has emerged wherein H1’s globular domain closes the nucleosome by crosslinking incoming and outgoing DNA, while the tail binds to linker DNA and neutralizes its negative charge.[8][12]

Many experiments addressing H1 function have been performed on purified, processed chromatin under low-salt conditions, but H1’s role in vivo is less certain. Cellular studies have shown that overexpression of H1 can cause aberrant nuclear morphology and chromatin structure, and that H1 can serve as both a positive and negative regulator of transcription, depending on the gene.[15][16][17] In Xenopus egg extracts, linker histone depletion causes ~2-fold lengthwise extension of mitotic chromosomes, while overexpression causes chromosomes to hypercompact into an inseparable mass.[18][19] Complete knockout of H1 in vivo has not been achieved in multicellular organisms due to the existence of multiple isoforms that may be present in several gene clusters, but various linker histone isoforms have been depleted to varying degrees in Tetrahymena, C. elegans, Arabidopsis, fruit fly, and mouse, resulting in various organism-specific defects in nuclear morphology, chromatin structure, DNA methylation, and/or specific gene expression.[20][21][22]


While most histone H1 in the nucleus is bound to chromatin, H1 molecules shuttle between chromatin regions at a fairly high rate.[23][24]

It is difficult to understand how such a dynamic protein could be a structural component of chromatin, but it has been suggested that the steady-state equilibrium within the nucleus still strongly favors association between H1 and chromatin, meaning that despite its dynamics, the vast majority of H1 at any given timepoint is chromatin bound.[25] H1 compacts and stabilizes DNA under force and during chromatin assembly, which suggests that dynamic binding of H1 may provide protection for DNA in situations where nucleosomes need to be removed.[26]

Cytoplasmic factors appear to be necessary for the dynamic exchange of histone H1 on chromatin, but these have yet to be specifically identified.[27] H1 dynamics may be mediated to some degree by O-glycosylation and phosphorylation. O-glycosylation of H1 may promote chromatin condensation and compaction. Phosphorylation during interphase has been shown to decrease H1 affinity for chromatin and may promote chromatin decondensation and active transcription. However, during mitosis phosphorylation has been shown to increase the affinity of H1 for chromosomes and therefore promote mitotic chromosome condensation.[19]


The H1 family in animals includes multiple H1 isoforms that can be expressed in different or overlapping tissues and developmental stages within a single organism. The reason for these multiple isoforms remains unclear, but both their evolutionary conservation from sea urchin to humans as well as significant differences in their amino acid sequences suggest that they are not functionally equivalent.[28][29][3] One isoform is histone H5, which is only found in avian erythrocytes, which are unlike mammalian erythrocytes in that they have nuclei. Another isoform is the oocyte/zygotic H1M isoform (also known as B4 or H1foo), found in sea urchins, frogs, mice, and humans, which is replaced in the embryo by somatic isoforms H1A-E, and H10 which resembles H5.[3][30][31][32] Despite having more negative charges than somatic isoforms, H1M binds with higher affinity to mitotic chromosomes in Xenopus egg extracts.[19]

Post-translational Modifications

Like other histones, the histone H1 family is extensively post-translationally modified (PTMs). This includes serine and threonine phosphorylation, lysine acetylation, lysine methylation and ubiquitination.[33] These PTMs serve a variety of functions but are less well studied than the PTMs of other histones.

See also


  1. ^ Ramakrishnan V, Finch JT, Graziano V, Lee PL, Sweet RM (March 1993). "Crystal structure of globular domain of histone H5 and its implications for nucleosome binding". Nature. 362 (6417): 219–23. Bibcode:1993Natur.362..219R. doi:10.1038/362219a0. PMID 8384699.
  2. ^ Kasinsky HE, Lewis JD, Dacks JB, Ausió J (January 2001). "Origin of H1 linker histones". FASEB Journal. 15 (1): 34–42. doi:10.1096/fj.00-0237rev. PMID 11149891.
  3. ^ a b c Izzo A, Kamieniarz K, Schneider R (April 2008). "The histone H1 family: specific members, specific functions?". Biological Chemistry. 389 (4): 333–43. doi:10.1515/BC.2008.037. PMID 18208346.
  4. ^ Jeon, Kwang W.; Berezney, Ronald (1995). Structural and functional organization of the nuclear matrix. Boston: Academic Press. pp. 214–7. ISBN 978-0-12-364565-4.
  5. ^ Finch JT, Klug A (June 1976). "Solenoidal model for superstructure in chromatin". Proceedings of the National Academy of Sciences of the United States of America. 73 (6): 1897–901. Bibcode:1976PNAS...73.1897F. doi:10.1073/pnas.73.6.1897. PMC 430414. PMID 1064861.
  6. ^ Thoma F, Koller T (September 1977). "Influence of histone H1 on chromatin structure". Cell. 12 (1): 101–7. doi:10.1016/0092-8674(77)90188-X. PMID 561660.
  7. ^ Thoma F, Koller T, Klug A (November 1979). "Involvement of histone H1 in the organization of the nucleosome and of the salt-dependent superstructures of chromatin". The Journal of Cell Biology. 83 (2 Pt 1): 403–27. doi:10.1083/jcb.83.2.403. PMC 2111545. PMID 387806.
  8. ^ a b van Holde K, Zlatanova J (October 1996). "What determines the folding of the chromatin fiber?". Proceedings of the National Academy of Sciences of the United States of America. 93 (20): 10548–55. Bibcode:1996PNAS...9310548V. doi:10.1073/pnas.93.20.10548. PMC 38190. PMID 8855215.
  9. ^ Routh A, Sandin S, Rhodes D (July 2008). "Nucleosome repeat length and linker histone stoichiometry determine chromatin fiber structure". Proceedings of the National Academy of Sciences of the United States of America. 105 (26): 8872–7. Bibcode:2008PNAS..105.8872R. doi:10.1073/pnas.0802336105. PMC 2440727. PMID 18583476.
  10. ^ Varshavsky AJ, Bakayev VV, Georgiev GP (February 1976). "Heterogeneity of chromatin subunits in vitro and location of histone H1". Nucleic Acids Research. 3 (2): 477–92. doi:10.1093/nar/3.2.477. PMC 342917. PMID 1257057.
  11. ^ Whitlock JP, Simpson RT (July 1976). "Removal of histone H1 exposes a fifty base pair DNA segment between nucleosomes". Biochemistry. 15 (15): 3307–14. doi:10.1021/bi00660a022. PMID 952859.
  12. ^ a b Allan J, Hartman PG, Crane-Robinson C, Aviles FX (December 1980). "The structure of histone H1 and its location in chromatin". Nature. 288 (5792): 675–9. Bibcode:1980Natur.288..675A. doi:10.1038/288675a0. PMID 7453800.
  13. ^ Staynov DZ, Crane-Robinson C (December 1988). "Footprinting of linker histones H5 and H1 on the nucleosome". The EMBO Journal. 7 (12): 3685–91. doi:10.1002/j.1460-2075.1988.tb03250.x. PMC 454941. PMID 3208745.
  14. ^ Bednar J, Horowitz RA, Grigoryev SA, Carruthers LM, Hansen JC, Koster AJ, Woodcock CL (November 1998). "Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin". Proceedings of the National Academy of Sciences of the United States of America. 95 (24): 14173–8. Bibcode:1998PNAS...9514173B. doi:10.1073/pnas.95.24.14173. PMC 24346. PMID 9826673.
  15. ^ Dworkin-Rastl E, Kandolf H, Smith RC (February 1994). "The maternal histone H1 variant, H1M (B4 protein), is the predominant H1 histone in Xenopus pregastrula embryos". Developmental Biology. 161 (2): 425–39. doi:10.1006/dbio.1994.1042. PMID 8313993.
  16. ^ Brown DT, Alexander BT, Sittman DB (February 1996). "Differential effect of H1 variant overexpression on cell cycle progression and gene expression". Nucleic Acids Research. 24 (3): 486–93. doi:10.1093/nar/24.3.486. PMC 145659. PMID 8602362.
  17. ^ Gunjan A, Alexander BT, Sittman DB, Brown DT (December 1999). "Effects of H1 histone variant overexpression on chromatin structure". The Journal of Biological Chemistry. 274 (53): 37950–6. doi:10.1074/jbc.274.53.37950. PMID 10608862.
  18. ^ Maresca TJ, Freedman BS, Heald R (June 2005). "Histone H1 is essential for mitotic chromosome architecture and segregation in Xenopus laevis egg extracts". The Journal of Cell Biology. 169 (6): 859–69. doi:10.1083/jcb.200503031. PMC 2171634. PMID 15967810.
  19. ^ a b c Freedman BS, Heald R (June 2010). "Functional comparison of H1 histones in Xenopus reveals isoform-specific regulation by Cdk1 and RanGTP". Current Biology. 20 (11): 1048–52. doi:10.1016/j.cub.2010.04.025. PMC 2902237. PMID 20471264.
  20. ^ Shen X, Yu L, Weir JW, Gorovsky MA (July 1995). "Linker histones are not essential and affect chromatin condensation in vivo". Cell. 82 (1): 47–56. doi:10.1016/0092-8674(95)90051-9. PMID 7606784.
  21. ^ Jedrusik MA, Schulze E (April 2001). "A single histone H1 isoform (H1.1) is essential for chromatin silencing and germline development in Caenorhabditis elegans". Development. 128 (7): 1069–80. PMID 11245572.
  22. ^ Lu X, Wontakal SN, Emelyanov AV, Morcillo P, Konev AY, Fyodorov DV, Skoultchi AI (February 2009). "Linker histone H1 is essential for Drosophila development, the establishment of pericentric heterochromatin, and a normal polytene chromosome structure". Genes & Development. 23 (4): 452–65. doi:10.1101/gad.1749309. PMC 2648648. PMID 19196654.
  23. ^ Misteli T, Gunjan A, Hock R, Bustin M, Brown DT (December 2000). "Dynamic binding of histone H1 to chromatin in living cells". Nature. 408 (6814): 877–81. Bibcode:2000Natur.408..877M. doi:10.1038/35048610. PMID 11130729.
  24. ^ Chen D, Dundr M, Wang C, Leung A, Lamond A, Misteli T, Huang S (January 2005). "Condensed mitotic chromatin is accessible to transcription factors and chromatin structural proteins". The Journal of Cell Biology. 168 (1): 41–54. doi:10.1083/jcb.200407182. PMC 2171683. PMID 15623580.
  25. ^ Bustin M, Catez F, Lim JH (March 2005). "The dynamics of histone H1 function in chromatin". Molecular Cell. 17 (5): 617–20. doi:10.1016/j.molcel.2005.02.019. PMID 15749012.
  26. ^ Xiao B, Freedman BS, Miller KE, Heald R, Marko JF (December 2012). "Histone H1 compacts DNA under force and during chromatin assembly". Molecular Biology of the Cell. 23 (24): 4864–71. doi:10.1091/mbc.E12-07-0518. PMC 3521692. PMID 23097493.
  27. ^ Freedman BS, Miller KE, Heald R (September 2010). Cimini D (ed.). "Xenopus egg extracts increase dynamics of histone H1 on sperm chromatin". PLOS ONE. 5 (9): e13111. Bibcode:2010PLoSO...513111F. doi:10.1371/journal.pone.0013111. PMC 2947519. PMID 20927327.
  28. ^ Steinbach OC, Wolffe AP, Rupp RA (September 1997). "Somatic linker histones cause loss of mesodermal competence in Xenopus". Nature. 389 (6649): 395–9. Bibcode:1997Natur.389..395S. doi:10.1038/38755. PMID 9311783.
  29. ^ De S, Brown DT, Lu ZH, Leno GH, Wellman SE, Sittman DB (June 2002). "Histone H1 variants differentially inhibit DNA replication through an affinity for chromatin mediated by their carboxyl-terminal domains". Gene. 292 (1–2): 173–81. doi:10.1016/S0378-1119(02)00675-3. PMID 12119111.
  30. ^ Khochbin S (June 2001). "Histone H1 diversity: bridging regulatory signals to linker histone function". Gene. 271 (1): 1–12. doi:10.1016/S0378-1119(01)00495-4. PMID 11410360.
  31. ^ Godde JS, Ura K (March 2008). "Cracking the enigmatic linker histone code". Journal of Biochemistry. 143 (3): 287–93. doi:10.1093/jb/mvn013. PMID 18234717.
  32. ^ Happel N, Doenecke D (February 2009). "Histone H1 and its isoforms: contribution to chromatin structure and function". Gene. 431 (1–2): 1–12. doi:10.1016/j.gene.2008.11.003. PMID 19059319.
  33. ^ Harshman SW, Young NL, Parthun MR, Freitas MA (November 2013). "H1 histones: current perspectives and challenges". Nucleic Acids Research. 41 (21): 9593–609. doi:10.1093/nar/gkt700. PMC 3834806. PMID 23945933.

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

linker histone H1 and H5 family Provide feedback

Linker histone H1 is an essential component of chromatin structure. H1 links nucleosomes into higher order structures Histone H1 is replaced by histone H5 in some cell types.

Literature references

  1. Ramakrishnan V, Finch JT, Graziano V, Lee PL, Sweet RM; , Nature 1993;362:219-223.: Crystal structure of globular domain of histone H5 and its implications for nucleosome binding. PUBMED:8384699 EPMC:8384699

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR005818

This entry represents the H15 domain.

Histone proteins have central roles in both chromatin organisation (as structural units of the nucleosome) and gene regulation (as dynamic components that have a direct impact on DNA transcription and replication). Eukaryotic DNA wraps around a histone octamer to form a nucleosome, the first order of compaction of eukaryotic chromatin. The core histone octamer is composed of a central H3-H4 tetramer and two flanking H2A-H2B dimers. Each of the core histone contains a common structural motif, called the histone fold, which facilitates the interactions between the individual core histones.

In addition to the core histones, there is a "linker histone" called H1 (or H5 in avian species). The linker histones present in all multicellular eukaryotes are the most divergent group of histones, with numerous cell type- and stage-specific variant. Linker histone H1 is an essential component of chromatin structure. H1 links nucleosomes into higher order structures. Histone H5 performs the same function as histone H1, and replaces H1 in certain cells. The structure of GH5, the globular domain of the linker histone H5 is known [ PUBMED:8384699 , PUBMED:3463990 ]. The fold is similar to the DNA-binding domain of the catabolite gene activator protein, CAP, thus providing a possible model for the binding of GH5 to DNA.

The linker histones, which do not contain the histone fold motif, are critical to the higher-order compaction of chromatin, because they bind to internucleosomal DNA and facilitate interactions between individual nucleosomes. In addition, H1 variants have been shown to be involved in the regulation of developmental genes. A common feature of this protein family is a tripartite structure in which a globular (H15) domain of about 80 amino acids is flanked by two less structured N- and C-terminal tails. The H15 domain is also characterised by high sequence homology among the family of linker histones. The highly conserved H15 domain is essential for the binding of H1 or H5 to the nucleosome. It consists of a three helix bundle (I-III), with a beta-hairpin at the C terminus. There is also a short three-residue stretch between helices I and II that is in the beta-strand conformation. Together with the C-terminal beta-hairpin, this strand forms the third strand of an antiparallel beta-sheet [ PUBMED:16345076 , PUBMED:8384699 , PUBMED:8218199 , PUBMED:14654695 ].

Proteins known to contain a H15 domain are:

  • - Eukaryotic histone H1. The histones H1 constitute a family with many variants, differing in their affinity for chromatin. Several variants are simultaneously present in a single cell. For example, the nucleated erythrocytes of birds contain both H1 and H5, the latter being an extreme variant of H1.
  • - Eukaryotic MHYST family of histone acetyltransferase. Histone acetyltransferases transfer an acetyl group from acetyl-CoA to the epsylon- amino group of lysine within the basic NH2-termini of histones, which bind the acidic phosphates of DNA [ PUBMED:15313893 ].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan HTH (CL0123), which has the following description:

This family contains a diverse range of mostly DNA-binding domains that contain a helix-turn-helix motif.

The clan contains the following 381 members:

AbiEi_3_N AbiEi_4 ANAPC2 AphA_like AraR_C Arg_repressor ARID ArsR B-block_TFIIIC B5 Bac_DnaA_C Baculo_PEP_N BetR BHD_3 BLACT_WH Bot1p BrkDBD BrxA BsuBI_PstI_RE_N C_LFY_FLO CaiF_GrlA CarD_CdnL_TRCF CDC27 Cdc6_C Cdh1_DBD_1 CDT1 CDT1_C CENP-B_N Costars CPSase_L_D3 Cro Crp CSN4_RPN5_eIF3a CSN8_PSD8_EIF3K CtsR Cullin_Nedd8 CUT CUTL CvfB_WH DBD_HTH DDRGK DEP Dimerisation Dimerisation2 DNA_binding_1 DNA_meth_N DpnI_C DprA_WH DsrC DsrD DUF1016_N DUF1133 DUF1153 DUF1323 DUF134 DUF1376 DUF1441 DUF1492 DUF1495 DUF1670 DUF1804 DUF1836 DUF1870 DUF2089 DUF2250 DUF2316 DUF2513 DUF2551 DUF2582 DUF3116 DUF3161 DUF3253 DUF3489 DUF3853 DUF3860 DUF3895 DUF3908 DUF433 DUF434 DUF4364 DUF4373 DUF4423 DUF4447 DUF4777 DUF480 DUF4817 DUF5635 DUF573 DUF5805 DUF6088 DUF6262 DUF6362 DUF6432 DUF6462 DUF6471 DUF722 DUF739 DUF742 DUF937 DUF977 E2F_TDP EAP30 eIF-5_eIF-2B ELL ESCRT-II Ets EutK_C Exc F-112 FaeA Fe_dep_repr_C Fe_dep_repress FeoC FokI_D1 FokI_dom_2 Forkhead FtsK_gamma FUR GcrA GerE GntR GP3_package HARE-HTH HemN_C HNF-1_N Homeobox_KN Homeodomain Homez HPD HrcA_DNA-bdg HSF_DNA-bind HTH_1 HTH_10 HTH_11 HTH_12 HTH_13 HTH_15 HTH_16 HTH_17 HTH_18 HTH_19 HTH_20 HTH_21 HTH_22 HTH_23 HTH_24 HTH_25 HTH_26 HTH_27 HTH_28 HTH_29 HTH_3 HTH_30 HTH_31 HTH_32 HTH_33 HTH_34 HTH_35 HTH_36 HTH_37 HTH_38 HTH_39 HTH_40 HTH_41 HTH_42 HTH_43 HTH_45 HTH_46 HTH_47 HTH_48 HTH_49 HTH_5 HTH_50 HTH_51 HTH_52 HTH_53 HTH_54 HTH_55 HTH_56 HTH_57 HTH_58 HTH_59 HTH_6 HTH_60 HTH_61 HTH_7 HTH_8 HTH_9 HTH_ABP1_N HTH_AraC HTH_AsnC-type HTH_CodY HTH_Crp_2 HTH_DeoR HTH_IclR HTH_Mga HTH_micro HTH_OrfB_IS605 HTH_PafC HTH_ParB HTH_psq HTH_SUN2 HTH_Tnp_1 HTH_Tnp_1_2 HTH_Tnp_2 HTH_Tnp_4 HTH_Tnp_IS1 HTH_Tnp_IS630 HTH_Tnp_ISL3 HTH_Tnp_Mu_1 HTH_Tnp_Mu_2 HTH_Tnp_Tc3_1 HTH_Tnp_Tc3_2 HTH_Tnp_Tc5 HTH_WhiA HxlR IBD IF2_N IRF KicB KilA-N Kin17_mid KORA KorB La LacI LexA_DNA_bind Linker_histone LZ_Tnp_IS481 MADF_DNA_bdg MAGE MARF1_LOTUS MarR MarR_2 MC6 MC7 MC8 MerR MerR-DNA-bind MerR_1 MerR_2 Mga Mnd1 MogR_DNAbind Mor MotA_activ MqsA_antitoxin MRP-L20 Mrr_N MukE Myb_DNA-bind_2 Myb_DNA-bind_3 Myb_DNA-bind_4 Myb_DNA-bind_5 Myb_DNA-bind_6 Myb_DNA-bind_7 Myb_DNA-binding Neugrin NFRKB_winged NOD2_WH NUMOD1 ORC_WH_C OST-HTH P22_Cro PaaX PadR PapB PAX PCI Penicillinase_R Phage_AlpA Phage_antitermQ Phage_CI_repr Phage_CII Phage_NinH Phage_Nu1 Phage_rep_O Phage_rep_org_N Phage_terminase PheRS_DBD1 PheRS_DBD2 PheRS_DBD3 PhetRS_B1 Pou Pox_D5 PqqD PRC2_HTH_1 PUFD PuR_N Put_DNA-bind_N pXO2-72 Raf1_HTH Rap1-DNA-bind Rep_3 RepA_C RepA_N RepB RepC RepL Replic_Relax RFX_DNA_binding Ribosomal_S18 Ribosomal_S19e Ribosomal_S25 Rio2_N RNA_pol_Rpc34 RNA_pol_Rpc82 RNase_H2-Ydr279 ROQ_II ROXA-like_wH RP-C RPA RPA_C RPN6_C_helix RQC Rrf2 RTP RuvB_C S10_plectin SAC3_GANP SANT_DAMP1_like SatD SelB-wing_1 SelB-wing_2 SelB-wing_3 SgrR_N Sigma54_CBD Sigma54_DBD Sigma70_ECF Sigma70_ner Sigma70_r2 Sigma70_r3 Sigma70_r4 Sigma70_r4_2 SinI SKA1 Ski_Sno SLIDE Slx4 SMC_Nse1 SMC_ScpB SoPB_HTH SpoIIID SRP19 SRP_SPB STN1_2 Stn1_C Stork_head Sulfolobus_pRN Suv3_N Swi6_N SWIRM Tau95 TBPIP TEA Terminase_5 TetR_N TFA2_Winged_2 TFIIE_alpha TFIIE_beta TFIIF_alpha TFIIF_beta Tn7_Tnp_TnsA_C Tn916-Xis TraI_2_C Trans_reg_C TrfA TrmB tRNA_bind_2 tRNA_bind_3 Trp_repressor UPF0122 UPF0175 Vir_act_alpha_C XPA_C Xre-like-HTH YdaS_antitoxin YidB YjcQ YokU z-alpha


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

Representative proteomes UniProt
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PP/heatmap 1            

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

Representative proteomes UniProt

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

Representative proteomes UniProt
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Arne Eloffson
Previous IDs: linker_histone;
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
Number in seed: 237
Number in full: 9442
Average length of the domain: 69.80 aa
Average identity of full alignment: 30 %
Average coverage of the sequence by the domain: 22.15 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.4 22.4
Trusted cut-off 22.4 22.4
Noise cut-off 22.3 22.3
Model length: 74
Family (HMM) version: 22
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Tree controls


The tree shows the occurrence of this domain across different species. More...


Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Linker_histone domain has been found. There are 34 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2K654 View 3D Structure Click here
A0A0P0W2V4 View 3D Structure Click here
A0A0P0WRW9 View 3D Structure Click here
A0A0R0EKB5 View 3D Structure Click here
A0A0R0HMY4 View 3D Structure Click here
A0A0R0I303 View 3D Structure Click here
A0A0R0JCA0 View 3D Structure Click here
A0A0R0JTK3 View 3D Structure Click here
A0A0R4IAV0 View 3D Structure Click here
A0A140LFZ1 View 3D Structure Click here
A0A140LGU1 View 3D Structure Click here
A0A140LGZ1 View 3D Structure Click here
A0A140LH11 View 3D Structure Click here
A0A140LH24 View 3D Structure Click here
A0A140LH34 View 3D Structure Click here
A0A140LH63 View 3D Structure Click here
A0A1D6GFH8 View 3D Structure Click here
A0A1D6GJA0 View 3D Structure Click here
A0A1D6GJA9 View 3D Structure Click here
A0A1D6I413 View 3D Structure Click here
A0A1D6L1W0 View 3D Structure Click here
A0A1D6NW49 View 3D Structure Click here
A0A1D8PR93 View 3D Structure Click here
A0A2R8PVA3 View 3D Structure Click here
A0A2R8Q0U0 View 3D Structure Click here
A0A2R8QPQ7 View 3D Structure Click here
A3KPR3 View 3D Structure Click here
A4QN90 View 3D Structure Click here
B0R0K9 View 3D Structure Click here
B4FIQ4 View 3D Structure Click here
B4FQA5 View 3D Structure Click here
B4FT40 View 3D Structure Click here
B6T2X7 View 3D Structure Click here
B6TGH8 View 3D Structure Click here
B7EMI6 View 3D Structure Click here
C0HIA3 View 3D Structure Click here
C4J4W6 View 3D Structure Click here
C6TI08 View 3D Structure Click here
D3ZBN0 View 3D Structure Click here
D3ZEG0 View 3D Structure Click here