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Review
. 2015 Mar 25;115(6):2296-349.
doi: 10.1021/cr5003529. Epub 2014 Oct 20.

Histones: At the Crossroads of Peptide and Protein Chemistry

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Free PMC article
Review

Histones: At the Crossroads of Peptide and Protein Chemistry

Manuel M Müller et al. Chem Rev. .
Free PMC article

Figures

Figure 1
Figure 1
Chromatin architecture in eukaryotic cells. (a) Structure of a mononucleosome. DNA (gray) is wrapped around two copies each of H2A (orange), H2B (red), H3 (blue), and H4 (green); pdb code: 1kx5. (b) Electrostatic surface rendering of a histone octamer. Highly cationic patches (blue) guide the trajectory of DNA wrapping. (c) Schematic representation of genome architecture.
Figure 2
Figure 2
Histone sequence features. (a) Histones contain a skewed amino acid composition. Amino acid frequencies are normalized to the average occurrence found in all proteins contained in the uniprot database (www.uniprot.org). Cationic residues, Arg, Lys; anionic, Asp, Glu; polar, Asn, Gln, Ser, Thr; aromatic, His, Phe, Trp, Tyr; aliphatic, Ile, Leu, Met, Val; Ala and Cys are plotted individually; the secondary structure breaking residues Gly and Pro are binned together. (b) Recurring sequence motifs in histone tails surrounding modified lysine residues.
Scheme 1
Scheme 1. Solid-Phase Peptide Synthesis (SPPS) Using the N-α-Boc-Protection Strategy
Figure 3
Figure 3
Synthesis of acetylated H4 peptides to define the substrate specificity of an HDAC. (a) Limited proteolysis of acetylated H4 yields long peptidic HDAC substrates. HATs = histone acetyltransferases. (b) Solid-phase peptide synthesis (SPPS) using a radiolabeled acetyllysine building block (inset) yields a hepta-peptide that is not an HDAC substrate. (c) A long synthetic peptide bearing two distinctly radio-labeled acetyl groups illustrates promiscuity in HDAC activity.
Figure 4
Figure 4
Recognition of acetyllysine residues by bromodomains. (a) Binding pocket of the GCN5 BD in complex with an H4 peptide acetylated at Lys16 (green). A hydrogen bond between Asn407 of the BD (black) and the acetyl group is indicated with a dotted line; pdb code: 1E6I. (b) Architecture of the double-BD module of TAFII250. The acetyllysine binding pocket of each lobe is indicated in red; pdb code: 1EQF. (c) Simultaneous binding of two acetyllysine residues by BD1 of Brdt. A synthetic H4 peptide bearing K5ac and K8ac is depicted in green with hydrogen-bonding networks indicated by dotted lines; pdb code: 2WP2. Surfaces in subfigures (a) and (c) are shown in electrostatic rendering (blue, positive; white, neutral; red, negative). Ordered water molecules are shown as red spheres.
Figure 5
Figure 5
PTM-selective antibodies as tools in chromatin biochemistry. (a) General outline of the chromatin immunoprecipitation (ChIP) workflow. (b) Production of site-specific acetyllysine antibodies using synthetic peptides. Specifically acetylated peptides are used to immunize rabbits to elicit a collection of antibodies that recognize defined acetylation marks. In this example, antibody selectivity was probed using the synthetic peptide substrates (right). Plus symbols denote a strong recognition, (+) stands for weak binding, whereas minus signs indicate no cross-reactivity. Data taken from ref (60).
Figure 6
Figure 6
Mechanism of class III HDACs (a) probed with histone peptides carrying analogues of acetyllysine (b). n.d. stands for not determined. Data taken from refs (62) and (63).
Scheme 2
Scheme 2. Solid-Phase Peptide Synthesis (SPPS) Using the N-α-Fmoc-Protection Strategy
Figure 7
Figure 7
Synthesis of methyllysine-containing peptides. (a) Commonly used activating agents and additives. (b) Standard methyllysine building blocks used for Fmoc-based SPPS.
Figure 8
Figure 8
Recognition of methyllysine. (a) Structures of the HP1 chromodomain in complex with methyllysine residues (pdb codes for K9me3, 1kne; K9me2, 1kna; K9me1, 1q3l) or in its apo form (right, pdb code: 1ap0). The CD is depicted in green, the ligand in yellow. Note that the apo-structure was solved with murine HP1 while the liganded structures were obtained from drosophila HP1, which contains a Tyr residue in place of Phe45. (b) Selective recognition of lower methylation states by the chromodomain of MSL3 (pdb code: 3m9p). The CD is depicted in cyan, the ligand in pink. For comparison, the corresponding residues in the HP1 CD are indicated in pale rendering. (c) Structure of tert-butylnorleucine (1), a trimethyllysine isostere. (d) Structure of a calix[4]arene receptor (2) for methyllysine-containing peptides.
Figure 9
Figure 9
Identification of new histone PTM binders. (a) Schematic of the workflow for peptide pull-downs of nuclear proteins. Modified peptides are immobilized on avidin beads and used to fish out specific binders such as the H3K4me3 binder BPTF. (b) Structure of the BPTF PHD finger (mauve) in complex with H3K4me3 (yellow, pdb code: 2f6j). An ion pair between Arg2 of histone H3 and an Asp residue of the PHD finger contributes to selectivity. (c) SILAC-based identification of methyllysine binders. Modified and control histone peptides are immobilized and incubated with isotopically labeled nuclear extracts. A hypothetical mass spectrum illustrating different selectivities of detected proteins is depicted on the right.
Figure 10
Figure 10
Mechanism-based histone demethylase inhibitors. Propargyllysine is oxidized by LSD1 via its FAD cofactor. The resulting Michael acceptor forms a covalent adduct with the reduced cofactor.
Figure 11
Figure 11
Methylarginine structure and recognition. (a) Isoforms of methylarginine residues. (b) Standard methylarginine building blocks for Fmoc-based SPPS. (c) Structure of the aromatic cage of the TDRD3 tudor domain (pdb code: 2lto). The Rme2a residue is colored in yellow, the specificity-determining tyrosine in pale green. (d) Structure of a synthetic Rme2a receptor isolated from a dynamic combinatorial library.
Figure 12
Figure 12
PAD4-catalyzed deimination and possibly demethylimination to citrulline. Whether mechanisms exist to convert citrulline back to arginine in the context of histones is unknown.
Figure 13
Figure 13
Building blocks for the synthesis of O-linked (a) and N-linked (b) phosphopeptides and their analogues.
Figure 14
Figure 14
Biochemical readout of histone phosphorylation. (a) Illustration of a meLys/pSer switch. Phosphorylation at H3S10 ejects the K9me3 binding protein HP1, and prevents K9 methylation by the methyltransferase Suv39h1. (b) Structure of 14-3-3γ (green, pdb code: 2c1j) in complex with an H3 peptide containing S10ph and K9ac (yellow). Hydrogen bonds are indicated by dotted lines.
Figure 15
Figure 15
Synthesis of mono-ADP-ribosylated peptides. (a) On-resin phosphorylation and AMP conjugation of an orthogonally protected ribosyl moiety. (b) Chemoselective ADP-ribose (inset) ligation to aminoxy-functionalized peptides. (c) ADP-ribose conjugates of N-methyl aminoxy-functionalized peptides retain the ribo-furanosyl-form. AMP = adenosine monophosphate, ADP = adenosine diphosphate.
Figure 16
Figure 16
Newly discovered lysine acylation marks. (a) Lysine crotonylation. (b) Lysine hydroxyisobutyrylation (6), and control isomers (710).
Figure 17
Figure 17
Proline isomerization. (a) Amino acid cis/trans equilibria. (b) Proposed switches through coupled Pro isomerization and Lys methylation to activate associated genes. Lys36 methyl marks are indicated as green spheres.
Figure 18
Figure 18
Cancer-derived H3K27M mutants inhibit PRC2 activity. (a) Molecular architecture of PRC2 according to Ciferri et al. (b) PRC2 inhibition by K27M causes aberrant gene expression. PRC2 serves to silence certain genes through its HMT activity (left). In K27M tumor cells (right), trimethylation at Lys27 is dramatically reduced, preventing gene repression. K27me3 marks are shown as green flags, K27M mutant as a red circle. (c) Structure of Lys, Met, and Nle.
Figure 19
Figure 19
Cross-linking strategies to study PRC2 regulation. (a) Structure and photo-cross-linking mechanism of photomethionine. (b) H3(23–34)K27photoMet cross-links to the catalytic subunit EZH2. The diazirine cross-linker is shown as a red triangle, the covalent adduct as a red line. (c) Structure and oxidative cross-linking mechanism of DOPA. (d) H3(35–42) cross-links to SUZ12. The DOPA cross-linker is shown as a red hexagon, the covalent adduct as a red line.
Figure 20
Figure 20
Photo-cross-linking strategies. (a) Structure and photoexcitation of p-benzoyl-phenylalanine. (b) Cross-linking-based workflow to identify proteins that are sensitive to the methylation state of H3K4.
Figure 21
Figure 21
Histone peptide microarrays. (a) Preparation of microarrays and protein binding assay. POI stands for protein of interest, AB for antibody. (b) Structure of the coupled TTD (light blue) and PHD (pale green) of UHRF1 (pdb code: 3ask). The H3 peptide trimethylated at residue 9 is depicted in yellow, the linker between the two modules in black. (c) HDAC assay using SAMDI. Xaa and Yaa denote any amino acid.
Figure 22
Figure 22
SPOT synthesis of histone peptide arrays on cellulose membranes. Xaa and Yaa denote any amino acid, pg stands for side chain protecting group.
Figure 23
Figure 23
One bead-one compound libraries of modified H3 and H4 tails.
Figure 24
Figure 24
In vitro translation of histone peptides. (a) Reassigned codons with corresponding amino-acyl-tRNAs. (b) Schematic representation of mRNA display with the puromycin-mediated attachment of the mRNA to the growing peptide chain.
Figure 25
Figure 25
Nucleosome and chromatin architecture. (a) Electrostatic surface rendering of the mononucleosome (pdb code: 1kx5). Cationic areas are colored in blue, anionic patches in red, the DNA backbone is drawn in gray. (b) Interaction of the acidic patch on H2A/H2B (red surface) with the H4 tail of a neighboring particle (yellow). (c) Crystal structure of a tetranucleosome array (pdb code: 1zbb). (d) Dodecanucleosome arrays fold into a two-start helix as suggested by a cryo-EM structural model (EMD-2600).
Figure 26
Figure 26
Nucleosome cross-linking. (a) Disulfide cross-linking from the H4 tail (green) to the acidic patch of H2A/H2B with engineered cysteines (black). (b) Structure of 4-azidophenacyl bromide (APB) and its reaction with cysteine. (c) Photo-cross-linking reveals the position of the H2A N-terminal tail. APB is attached to an engineered cysteine within the H2A tail (black), the cross-linking site on DNA is shown in black.
Figure 27
Figure 27
Site-directed footprinting to map nucleosome positioning. (a) Activated disulfide reagent (7) to attach an EDTA derivative to cysteine residues (top) and hydroxyl radical generation by the Fenton reaction employing Fe(II) (bottom). (b) Model of the preferred cleavage site (red) upon introducing a sensitizer at H4S47C (yellow). The nucleosome dyad is indicated with a white arrow. (c) Structure of N-(1,10-phenanthroline-5-yl)iodoacetamide (8) in complex with Cu(I).
Figure 28
Figure 28
Spectroscopic characterization of nucleosomes and histones. (a) FRET assay to investigate DNA breathing. DNA (gray) is labeled with Cy3 (green star), H3 V35C (black), with Cy5 (red star). DNA unwrapping increases the distance between the fluorophores, leading to a loss in FRET signal. (b) Structure of cysteine-reactive Cy5-maleimide. (c) Structure of the MTSL spin label. (d) Distance measurement with PELDOR between spin labels (arrow) installed at H3Q125C. H3 is drawn in blue, H4 in green. (e) Asymmetric positioning of H1 (blue) on the nucleosome core particle. A spin label (arrow) placed at H3K37C perturbs NMR signals in its vicinity (dashed sphere).
Figure 29
Figure 29
Structure and applications of methyllysine analogues. (a) Synthesis of methyllysine analogues by cysteine alkylation. (b) Comparison between methyllysine and a thioether analogue. (c and d) Subtle local changes in nucleosome structure upon histone lysine methylation. Modified nucleosomes are depicted in light colors (H3K79Cme2 in light blue, pdb code 3c1c in (c); H4K20Cme3 in pale green, pdb code 3c1b in (d)). Unmodified versions are shown in corresponding dark tones (pdb code: 1kx5). Yellow arrows indicate modified residues. (e) Model of the structure of a nucleosome containing H3K36me3 (yellow arrow) in complex with the PSIP1 PWWP domain (the backbones of neutral, basic, and acidic side chains are shown in white, blue, and red, respectively; pdb code: 3ZH1).
Figure 30
Figure 30
Model for HP1 binding to heterochromatin domains. The chromodomain (CD, blue) binds to H3K9me3 (red flag), although this interaction is weak and dynamic. Stable dimerization through the chromoshadow domain (CSD, light blue and pale green) provides a polyvalent scaffold for chromatin binding. Plasticity is granted by the flexibility of the H3 tail and the linker between the HP1 domains (red arrows).
Figure 31
Figure 31
Synthesis of (a,b) acetyllysine and (c) methylarginine analogues from cysteine-containing histones.
Figure 32
Figure 32
Incorporation of nonstandard amino acids (blue) into proteins in E. coli. An engineered orthogonal aaRS (top) charges a cognate tRNA with a designated amino acid, but does not interact with natural amino acids or E. coli tRNAs (bottom). Similarly, neither the exogenously introduced tRNA (here from M. barkeri) nor the nonstandard amino acid is recognized by any aaRS from E. coli (gray). Translation of the unnatural amino acid occurs opposite an amber stop codon (UAG).
Figure 33
Figure 33
K56ac (black) increases breathing of nucleosomal DNA.
Figure 34
Figure 34
Strategies to genetically encode methyllysine residues. (a) Incorporation of protected Kme1-species. (b) Protection-modification scheme to access Kme2-containing proteins. Boc-protected lysine is incorporated into histones through amber suppression. Orthogonal protection of other lysine residues, followed by removal of the Boc group and reductive alkylation enables site-specific modification. Global deprotection then provides the desired histone. TFMSA = trifluoromethylsulfonic acid, TFA = trifluoroacetic acid, DMS = dimethylsulfide.
Figure 35
Figure 35
Biosynthetic incorporation of PTM analogues through dehydroalanine intermediates. Dehydroalanine can be generated through selenoxide pyrolysis (left) or cysteine-specific reagents (right). Michael addition of thiols to dehydroalanine generates PTM analogues, albeit with loss of stereochemical information.
Figure 36
Figure 36
Schematic of the signaling cascade that controls chromatin condensation during mitosis. Decompacted chromatin, partially labeled with a photo-cross-linker (BPA, red star), is acetylated at H4K16 (yellow flag). Upon entry into M phase, aurora B kinase phosphorylates H3S10 (blue lollipop), which recruits the HDAC Hst2p (blue). Once H4K16 is deacetylated, chromatin compacts, observed by an H2A–H4 cross-link (green star).
Figure 37
Figure 37
Mechanism of native chemical ligation (NCL).
Figure 38
Figure 38
Protein semisynthesis by native chemical ligation.
Figure 39
Figure 39
Comparison of peptide α-thioester synthesis by Boc- (a) and Fmoc-SPPS (b–e). (a) Synthesis of peptide α-thioesters on a mercaptopropionic acid linker by Boc-SPPS. (b) Direct conversion of a protected peptide acid into an α-thioester. (c) Latent thioester synthesis on a 2-hydroxy-3-mercaptopropionic acid linker. (d) α-Thioester synthesis through an acylthiourea intermediate. (e) Acyl-hydrazide method for α-thioester synthesis. Pg = protecting group.
Figure 40
Figure 40
Semisynthesis of H3S10ph. A synthetic peptide is converted into an α-thioester in solution with HBTU and benzyl mercaptan (top). Simultaneously, a recombinant fragment with an N-terminal cysteine residue (in place of Thr32) is prepared by site-specific proteolysis using Factor Xa (middle). Joining of the two fragments by NCL yields full-length H3 site-specifically phosphorylated at Ser10. A T32C mutation remains at the ligation junction (below). pg = protecting group.
Figure 41
Figure 41
Strategies to fix ligation scars in histone semisyntheses. (a) Conversion of Cys to Ala by desulfurization with Raney nickel in the semisynthesis of H3K9me3. (b) Alkylation of cysteine with bromoethylamine to produce thialysine in the semisynthesis of H4K16ac. (c) Radical-based desulfurization in the semisynthesis of H2B-S14ph.
Figure 42
Figure 42
Intein-mediated protein splicing. (a) Mechanism of intein autoprocessing. (b) Recombinant preparation of a protein α-thioester using a mutated intein. Thiolysis is mediated by a large excess of soluble thiol, such as sodium 2-mercaptoethanesulfonate (MesNa).
Figure 43
Figure 43
Preparation of modified histones by EPL. (a) Location of selected residues at the DNA binding surface. Residues on H3 and H4 are indicated with blue and green arrows, respectively. For clarity, labels are only placed on one copy of each histone. (b) Semisynthesis of H3 with acetyl marks close to the C-terminus using the native C110 for NCL. (c) EPL strategy to synthesize H4K77,79ac via an Ala76Cys mutation.
Figure 44
Figure 44
Streamlined expressed protein ligation to synthesize H2B-K120ac. Intein self-assembly is harnessed for affinity purification in a column-format. α-Thioester intermediates are subsequently captured by washing the column with excess thiols. The isolated H2B α-thioester is condensed with a synthetic peptide containing an N-terminal cysteine and the K120ac modification. The ligation product is subsequently desulfurized to render the process traceless.
Figure 45
Figure 45
Thiolated amino acid derivatives used for NCL.
Figure 46
Figure 46
Histone semisynthesis using a thioacid capture strategy. A truncated histone-intein conjugate is converted to a thioacid with H2S (left). This fragment is coupled with a C-terminal peptide, activated as an asymmetric disulfide (right). Disulfide exchange is followed by an intramolecular acyl shift and reduction to a native cysteine residue.
Figure 47
Figure 47
Histone semisynthesis using an engineered Sortase variant.
Figure 48
Figure 48
Multistep histone synthesis. (a) Total synthesis of H3K56ac using a three-step NCL procedure. (b) Total synthesis of H3K9me3 using Cys-Pro ester fragments, joined by NCL and direct aminolysis in the presence of Ag+ ions. (c) Three-piece semisynthesis to generate H3R42me2a. Initially, two synthetic peptides are joined by NCL. Subsequent activation of a C-terminal acyl hydrazide by oxidation enables a second NCL step to attach a recombinant fragment. pg denotes protecting groups.
Figure 49
Figure 49
Auxiliary-based semisynthesis of uH2B. (a) Site-specific ubiquitylation of histone peptides. An amino-thiol ligation auxiliary permits ligation of a ubiquitin α-thioester to a glycine residue attached to the side-chain of Lys120. (b) Semisynthesis of native, full-length uH2B via a two-step ligation. MesNa = sodium 2-mercaptoethanesulfonate, TCEP = tris(2-carboxyethyl)phosphine.
Figure 50
Figure 50
Streamlined semisyntheses of ubiquitylated histones. (a) Synthesis of H2B-K120ub containing the G76A mutation in ubiquitin. This mutation enables introduction of residue 76 of ubiquitin as a cysteine and subsequent NCL with a ubiquitin α-thioester. Finally, desulfurization converts Cys76 into an alanine residue. (b) Synthesis of H2A-K119ub containing the G76A mutation in ubiquitin. A penicillamine moiety permits NCL at a valine residue. (c) Disulfide-based conjugation of ubiquitin to H2B-K120C. In this approach, the ubiquitin α-thioester is reacted with cysteamine (top) and coupled to histones activated as disulfides (below), thus yielding disulfide-bonded analogues of H2B-K120ub (H2B-K120ubSS).
Figure 51
Figure 51
Plasticity in the stimulation of Dot1 by histone ubiquitylation. The canonical ubiquitylation site of H2B is indicated in black (K120, white arrow), permissive sites in green (H2A-G22 and H2B-K125), prohibitive sites in red (H2B-K108 and H2B-K116). The substrate residue (H3K79) of Dot1 is highlighted in blue.
Figure 52
Figure 52
Homo-FRET assay to monitor chromatin compaction. In the extended conformation, fluorescein labels (yellow stars) are far apart, thus limiting the amount of homo-FRET. Upon compaction, the distance between fluorophores is decreased, resulting in homo-FRET, which is detected by a reduction in the steady-state anisotropy (SSA) of the system.
Figure 53
Figure 53
Stepwise total synthesis of H2B-K34ub. This convergent ligation strategy involving four NCL steps commences with the synthesis of orthogonally protected histone H2B (top to bottom right) and finishes with ubiquitin conjugation and desulfurization (bottom left).
Figure 54
Figure 54
Bivalent recognition of doubly modified mononucleosomes by BPTF. The PHD finger of BPTF binds to H3K4me3 (gray arrows). In a nucleosomal context, this binding is reinforced through the recognition of H4K16ac by the adjacent bromodomain (black arrow).
Figure 55
Figure 55
Preparation and application of asymmetric mononucleosomes. (a) Synthesis of asymmetrically modified nucleosomes using a tagged, modified copy of H3 and an excess of an unmodified version. (b) The SAGA-complex is stimulated by its own mark. Nucleosomes that can only be acetylated on one H3 tail (tail-less and Lys9,14,18,23Ala) are poor SAGA substrates (gray arrows). Asymmetrically acetylated nucleosomes (right) recruit SAGA (dashed arrow) to promote acetylation of the unmodified H3 tail.
Figure 56
Figure 56
Nucleosome asymmetry in vivo. (a) Assembly of asymmetric H3/H4 tetramers using a tandem affinity tag strategy. (b) Distribution of H3K27 methyl marks in ES cells into symmetric and asymmetric mononucleosomes. (c) Bivalent domains consist of asymmetric nucleosomes with one H3 tail di- or trimethylated at Lys4, and another tail marked with K27me2/3.
Figure 57
Figure 57
Oligonucleosome arrays. (a) Synthesis of asymmetric dinucleosomes using nonpalindromic DNA overhangs and their application in studying histone-DNA contacts. Cross-links are detected through a gel-shift of the 32P-labeled DNA. (b) BPTF binds its marks (H3K4me3, blue flag, and H4K16ac, green circle) in a mononucleosomal context (black arrow). (c) H2B-K120ub stimulates Dot1 in cis (black arrow), but not toward methylation of adjacent nucleosomes. (d) Clr4/Suv39-mediated spreading of the heterochromatin-associated H3K9me3 mark (red flag). (e) Rpd3s deacetylation is stimulated by H3K36 methylation (orange flag) in an intra- and internucleosomal fashion. Note that Rpd3S recognizes dinucleosomes more readily than similarly modified mononucleosomes.
Figure 58
Figure 58
Identification of PTM-binding factors using modified chromatin as bait. (a) Synergies and antagonisms between DNA and histone methylation recognition. (b) Peptide- and chromatin-based probes reveal partially overlapping interactors. Here only a few examples are shown: BPTF and CHD4 are associated with chromatin remodeling, ING1 is a transcriptional regulator, TFIID is a general transcription factor complex, SIN3 is a histone deacetylase, PCAF and CDYL are histone acetyltransferases, HP1 is a “glue” for heterochromatin, UHRF is a recruiter of DNA methyltransferase, and NUP93 is a member of the nuclear pore. (c) Examples of H2B-K120ub-binding complexes. (d) Synthesis of a hydrolase-resistant H2B-K120ub analogue.
Figure 59
Figure 59
Schematic overview of a screening platform based on DNA-barcoded nucleosome libraries. Recombinant and semisynthetic histones are refolded into >50 different octamers in parallel, and assembled into mononucleosomes with barcoded DNA. Upon pooling, aliquots of the library are subjected to biochemical assays involving a pull-down step to enrich variants that exhibit certain traits. Subsequently, nucleosomal DNA is isolated and analyzed by next generation sequencing to provide a semiquantitative readout of hundreds to thousands of experiments.
Figure 60
Figure 60
Diagram of PTMs and their analogues that have been site-specifically incorporated into histones (as of September 2014). For clarity, connections are shown only to one copy of each histone.

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