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PubMed2005

Structural basis for vertebrate filamin dimerization.

Filamins are essential in cell motility and many developmental processes. They are large actin cross linking proteins that contain actin binding domains in their N termini and a long rod region constructed from 24 tandem Ig domains. Dimerization is crucial for the actin crosslinking function of filamins and requires the most C-terminal Ig domain. We describe here the crystal structure of this 24th Ig domain (Ig24) of human filamin C and show how it mediates dimerization. The dimer interface is novel and quite different to that seen in the Dictyostelium discoideum filamin analog. The sequence signature of the dimerization interface suggests that the C-terminal domains of all vertebrate filamins share the same dimerization mechanism. Furthermore, we show that point mutations in the dimerization interface disrupt the dimer and that the dissociation constant for recombinant Ig24 is in the micromolar range.

Actins↗
PubMed1999

Appearance of sodium dodecyl sulfate-stable amyloid beta-protein (Abeta) dimer in the cortex during aging.

We previously noted that some aged human cortical specimens containing very low or negligible levels of amyloid beta-protein (As) by enzyme immunoassay (EIA) provided prominent signals at 6 approximately 8 kd on the Western blot, probably representing sodium dodecyl sulfate (SDS)-stable Abeta dimer. Re-examination of the specificity of the EIA revealed that BAN50- and BNT77-based EIA, most commonly used for the quantitation of Abeta, capture SDS-dissociable Abeta but not SDS-stable Abeta dimer. Thus, all cortical specimens in which the levels of Abeta were below the detection limits of EIA were subjected to Western blot analysis. A fraction of such specimens contained SDS-stable dimer at 6 approximately 8 kd, but not SDS-dissociable A(beta) monomer at approximately 4 kd, as judged from the blot. This A(beta) dimer is unlikely to be generated after death, because (i) specimens with very short postmortem delay contained the A(beta) dimer, and (ii) until 12 hours postmortem, such SDS-stable A(beta) dimer is detected only faintly in PDAPP transgenic mice. The presence of A(beta) dimer in the cortex may characterize the accumulation of A(beta) in the human brain, which takes much longer than that in PDAPP transgenic mice.

Adult↗
PubMed2003

A kinase anchoring protein (AKAP) interaction and dimerization of the RIalpha and RIbeta regulatory subunits of protein kinase a in vivo by the yeast two hybrid system.

Protein kinase A (PKA) regulatory (R) subunits dimerize through an N-terminal motif. Such dimerization is necessary for binding to PKA anchoring proteins (AKAPs) and targeting of PKA to its site of action. In the present study, we used the yeast two-hybrid system as an in vivo bio-reporter assay and analyzed the formation of homo- and heterodimeric complexes of RIalpha and RIbeta as well as AKAP binding of RI dimers. Native polyacrylamide gel electrophoresis (PAGE) of yeast extracts confirmed the two-hybrid data. Both RIalpha- and RIbeta homodimers as well as an RIalpha:RIbeta heterodimer were observed. Single, double and one triple mutation were introduced into the RIalpha and RIbeta subunits and dimerization properties of the mutants were analyzed. Consistent with previous reports, RIalpha(C37H) dimerized, although the disulfide bridges were disrupted, whereas the additional mutation of F47 or F52 abolished the dimerization. Corresponding mutations (C38H, F48A, F53A) in RIbeta were not sufficient to abolish the RIbeta dimerization, indicating that additional or other amino acids are important. RIalpha:RIbeta heterodimers of the mutants were formed at intermediate stringency. Analysis of ternary complexes by the yeast two-hybrid system revealed that RIalpha and RIbeta homodimers as well as an RIalpha:RIbeta heterodimer and several of the mutants were able to bind to the R-binding domain of AKAP149/D-AKAP1. Furthermore, an RIbeta:AKAP149 complex was identified following introduction of RIbeta into HEK293 cells. Importantly, RIbeta revealed AKAP binding properties similar to those of RIalpha, indicating that RIbeta holoenzymes may be anchored.

A Kinase Anchor Proteins↗
PubMed2003

A molecular dynamics investigation of mono and dimeric states of the outer membrane enzyme OMPLA.

OMPLA is a phospholipase found in the outer membranes of many Gram-negative bacteria. Enzyme activation requires calcium-induced dimerisation plus bilayer perturbation. As the conformation of OMPLA in the different crystal forms (monomer versus dimer; with/without bound Ca(2+)) is remarkably similar we have used multi-nanosecond molecular dynamics (MD) simulations to probe possible differences in conformational dynamics that may be related to enzyme activation. Simulations of calcium-free monomeric OMPLA, of the Ca(2+)-bound dimer, and of the Ca(2+)-bound dimer with a substrate analogue covalently linked to the active site serine have been performed, all with the protein embedded in a phospholipid (POPC) bilayer. All simulations were stable, but differences in the dynamic behaviour of the protein between the various states were observed. In particular, the stability of the active site and the hydrophobic substrate-binding cleft varied. Dimeric OMPLA is less flexible than monomeric OMPLA, especially around the active site. In the absence of bound substrate analogue, the hydrophobic substrate-binding cleft of dimeric OMPLA collapses. A model is proposed whereby the increased stability of the active site in dimeric OMPLA is a consequence of the local ordering of water around the nearby calcium ion. The observed collapse of the substrate-binding cleft may explain the experimentally observed occurrence of multiple dimer conformations of OMPLA, one of which is fully active while the other shows significantly reduced activity.

Bacterial Outer Membrane Proteins↗
PubMed2003

Mutagenesis of the dimer interface residues of tethered and untethered HIV-1 protease result in differential activity and suggest multiple mechanisms of compensation.

As is the case for all retroviruses, the protease of HIV-1 is only functional as a homodimer; dimerization of two protease monomers results in the formation of the enzyme active site. This dimer structure is supported primarily by interactions between the first four amino-terminal and the last four carboxy-terminal amino acids. These eight amino acids form a beta-sheet in which hydrophobic residues are oriented towards the core of the molecule and polar residues are directed towards the solvent. Although the structure of the dimer interface has been determined, the forces that support dimerization have not been fully characterized. Here, we describe a tethered construct in which two protease monomers are joined by a 5 amino acid linker. We evaluate the relative role of each dimer interface residue in functional homo- and heterodimers. Our studies indicate that the hydrophobic residues of the dimer interface are particularly important in maintaining enzyme activity and that enzyme activity is more sensitive to substitutions of the C-terminal amino acids. Further, we demonstrate that the presence of the tether is able to compensate for mutations within the dimer interface that inactivate the enzyme.

Amino Acid Substitution↗
PubMed2000

Antimetastatic properties and DNA interactions of the novel class of dimeric Ru(III) compounds Na2[[trans-RuCl4(Me2SO)]2(mu-L)] (L = ditopic, non-chelating aromatic N-ligand). A preliminary investigation.

A novel class of dianionic Ru(III) dimers of formula Na2[[trans-RuCl4(Me2SO)]2(mu-L)], with L = pyrazine (pyz, 1), pyrimidine (pym, 2), 4,4'-bipyridine (bipy, 3), and 1,2-bis(4-pyridine) ethane (etbipy, 4), was developed by us with the specific aim of assessing their antitumor properties. The dimers are in fact structurally related to the antimetastatic mononuclear compound (ImH) [trans-RuCl4(Me2SO)(Im)] (NAMI-A, Im = imidazole). Preliminary results concerning the antineoplastic activity of 1-4 against the murine MCa carcinoma model, a tumor which spontaneously metastasizes in the lungs, are reported. Similarly to what is normally observed with NAMI-A, the treatment with the dimeric complexes was scarcely effective against the growth of the primary tumor. However, dimers 1, 2, and 4 reduced very effectively the number and, in particular, the weight of lung metastases (to about 5% with respect to controls); in particular, Na2[[trans-RuCl4(Me2SO)]2(mu-etbipy)] (4) was as effective as NAMI-A in reducing the spontaneous metastases at a dosage which, in terms of moles of ruthenium, is about 3.5 times lower compared to that normally used for NAMI-A. Furthermore, in vitro tests showed that dimers 1-4 are capable of forming interstrand cross-links with linearized plasmidic DNA in a time-dependent manner. All the dimeric species are more active in inducing cross-links compared to NAMI-A, and the dimer bridged by the etbipy ligand (4) is the most effective among those tested.

Animals↗
PubMed2000

Characterization of chloroquine-hematin mu-oxo dimer binding by isothermal titration calorimetry.

Numerous studies indicate that a key feature of chloroquine's (CQ) antimalarial activity is its interaction with hematin. We now characterize this CQ-hematin interaction in detail using isothermal titration calorimetry (ITC). Between pH 5.6 and 9.0, association constants (K(a) values) for enthalpy-driven CQ-hematin mu-oxo dimer binding fell in the narrow range of 2.3-4.4 x 10(5) M(-1). It is therefore probable that CQ-hematin mu-oxo dimer binding affinity does not diminish at the pH range (4.8-5.4) of the parasite food vacuole. The binding affinity was unaffected by high salt concentrations, suggesting that ionic interactions do not contribute significantly to this complexation. With increasing ionic strength, the entropic penalty of CQ-hematin mu-oxo dimer binding decreased accompanied by increased hematin mu-oxo dimer aggregation. A stoichiometry (n) of 1:4 in the pH range 6.5-9.0 indicates that CQ binds to two hematin mu-oxo dimers. At pH 5.6, a stoichiometry of 1:8 suggests that CQ binds to an aggregate of four hematin mu-oxo dimers. This work adds further evidence supporting the hypothesis that CQ impedes hematin monomer incorporation into hemozoin by producing a forward shift in the hematin monomer-hematin mu-oxo dimer equilibrium, contributing to a destructive accumulation of soluble forms of hematin in the parasite and leading to its death by hematin poisoning.

Antimalarials↗
PubMed2002

New chemical and biological aspects of artemisinin-derived trioxane dimers.

Joining two 10-deoxoartemisinin trioxane units via a p-diacetylbenzene linker produces new C-10 non-acetal dimers and. 1H NMR spectroscopy allows unambiguous assignment of the stereochemistry at C-10 in these dimers. Successful replacement of both carbonyl oxygen atoms in these diketone dimers by fluorine atoms produces new tetrafluorinated dimers and. Each dimer was evaluated in vitro for antimalarial, antiproliferative, and antitumor activities; ketone dimers and, more than fluorinated dimers and, are promising for chemotherapy of both malaria and cancer.

Artemisinins↗
PubMed1998

Inhibiting the dimeric restriction endonuclease EcoRI using interfacial helical peptides.

BACKGROUND: Many enzymes are active only in a dimeric form, including a variety of type II restriction endonucleases. Disruption of subunit interactions is therefore a potential method for multimeric enzyme inhibition. EcoRI is a homodimeric restriction endonuclease, the dimeric interface of which consists of a four-helix bundle. We set out to design helical peptides to interact with this interface and block dimer formation, thus rendering EcoRI inactive. RESULTS: Here we describe two synthetic, helical peptides based on the interfacial region of EcoRI. Both peptides inhibit the enzyme, but the peptide derived from the alpha 4 helix of EcoRI had both a higher helical content and better efficacy than a variant peptide, alpha 4(Leu), that has three Ile-->Leu mutations (IC50 values of 27 microM and 90 microM, and helical contents of 29% and 10%, respectively). Size-exclusion chromatography confirmed that the alpha 4 peptide disrupted dimerization of EcoRI, and circular dichroism indicated that EcoRI remained folded upon binding to alpha 4. Inhibition with alpha 4 and alpha 4(Leu) was shown to be specific for EcoRI, as the dimeric restriction enzyme PvuII was not affected by the peptides. CONCLUSIONS: Interfacial peptide inhibitors of the dimeric EcoRI were obtained that both inhibit dimerization and endonuclease activity. The peptide sequence with a preference for a helical conformation was a more effective inhibitor, presumably because the more preorganized state enhanced interactions with the helical interface of EcoRI. The specific nature of this endonuclease-peptide interaction was also confirmed. The potential of this strategy for inhibiting other enzyme classes is currently being addressed.

Chromatography, Gel↗
PubMed1999

A role for TBP dimerization in preventing unregulated gene expression.

The recruitment of the TATA box-binding protein (TBP) to promoters in vivo is often rate limiting in gene expression. We present evidence that TBP negatively autoregulates its accessibility to promoter DNA in yeast through dimerization. The crystal structure of TBP dimers was used to design point mutations in the dimer interface. These mutants are impaired for dimerization in vitro, and in vivo they generate large increases in activator-independent gene expression. Overexpression of wild-type TBP suppresses these mutants, possibly by heterodimerizing with them. In addition to loss of autorepression, dimerization-defective TBPs are rapidly degraded in vivo. Direct detection of TBP dimers in vivo was achieved through chemical cross-linking. Taken together, the data suggest that TBP dimerization prevents unregulated gene expression and its own degradation.

Amino Acid Substitution↗
PubMed2004

A mechanistic study of enantiomeric separation with vancomycin and balhimycin as chiral selectors by capillary electrophoresis. Dimerization and enantioselectivity.

The role of the sugar moiety of glycopeptide antibiotics in chiral recognition was investigated with capillary electrophoresis. Two glycopeptide antibiotics, vancomycin and balhimycin, were employed as models since they possess the same aglycon and almost identical sugar moieties, however, with different attachment sites to the aglycon. The observed enantioselectivity of balhimycin for dansylated alpha-amino acids is 2.6 times higher than that of vancomycin. Blocking of the sugar amino group of balhimycin by N-carbamoylation reaction with KOCN led to a significantly decreased enantioselectivity compared to vancomycin, which remained almost the same upon carbamoylation. These results suggest a major role of the amino sugar together with its site of attachment to the aglycon. A dimerization-based mechanism is proposed to explain this phenomenon due to the fact that the dimerization properties of glycopeptides are similarly related to their glycosylation patterns; e.g., the dimerization constant of balhimycin is 78 times higher than that of vancomycin. Furthermore, the dimerization of glycopeptides promotes their affinity to carboxyl-containing ligands via cooperativity effects between the dimerization and the formation of glycopeptide-ligand complexes. The higher dimer stability probably leads to a more favorable conformation for chiral recognition. Thus, it is concluded that a weakened dimerization of N-carbamoylated balhimycin results in a decreased enantioselectivity.

Amino Acids↗
PubMed2000

SecA folds via a dimeric intermediate.

Though many proteins in the cell are large and multimeric, their folding has not been extensively studied. We have chosen SecA as a folding model because it is a large, homodimeric protein (monomer molecular mass of 102 kDa) with multiple folding domains. SecA is the ATPase for the Sec-dependent preprotein translocase of many bacteria. SecA is a soluble protein that can penetrate into the membrane during preprotein translocation. Because SecA may partially unfold prior to its insertion into the membrane, studies of its stability and folding pathway are important for understanding how it functions in vivo. Kinetic folding transitions in the presence of urea were monitored using circular dichroism and tryptophan fluorescence, while equilibrium folding transitions were monitored using the same techniques as well as a fluorescent ATP analogue. The reversible equilibrium folding transition exhibited a plateau, indicating the presence of an intermediate. Based on the data presented here, we propose a three-state model, N(2) if I(2) if 2U, where the native protein unfolds to a dimeric intermediate which then dissociates into two unfolded monomers. The SecA dimer was determined to have an overall stability (DeltaG) of -22.5 kcal/mol. We also investigated the stability of SecA using analytical ultracentrifugation equilibrium and velocity sedimentation, which again indicated that native or refolded SecA was a stable dimer. The rate-limiting step in the folding pathway was conversion of the dimeric intermediate to the native dimer. Unfolding of native, dimeric SecA was slow with a relaxation time in H(2)O of 3.3 x 10(4) s. Since SecA is a stable dimer, dissociation to monomeric subunits during translocation is unlikely.

Adenosine Triphosphatases↗
PubMed2000

Detergent-solubilized bovine cytochrome c oxidase: dimerization depends on the amphiphilic environment.

The extent to which bovine cytochrome c oxidase (COX) dimerizes in nondenaturing detergent environments was assessed by sedimentation velocity and equilibrium. In contrast to generally accepted opinion, the COX dimer is difficult to maintain and is the major oligomeric form only when COX is solubilized with a low concentration of dodecylmaltoside, i.e., approximately 1 mg/mg protein. The dimer form is intrinsically unstable and dissociates into monomers with increased detergent concentration, i.e., >5 mg/mg protein. The structure of the solubilizing detergent, however, greatly alters detergent effectiveness by inducing either monomerization or aggregation. Triton X-100 is most effective at solubilizing COX, but it destabilizes COX dimers, even at low concentration. Undecylmaltoside, decylmaltoside, and octaethyleneglycolmonododecyl ether (C(12)E(8)) are less effective at solubilizing COX. Each prevents COX aggregation at high detergent concentration, but also destabilizes the COX dimer. Other detergents, e.g., Tween 20, sodium cholate, sodium deoxycholate, CHAPS, or CHAPSO, are completely ineffective COX solubilizers and do not prevent aggregation even at 10-40 mg/mL. The transition from dimers to monomers depends on many factors other than detergent structure and concentration, e.g., protein concentration, phospholipid content and pH. We conclude that the intrinsic dimeric structure of COX can be maintained only after solubilization with low concentrations of dodecylmaltoside at near neutral pH, and even then precautions must be taken to prevent its dissociation into monomers.

Animals↗
PubMed1991

Effect of base, pentose, and phosphodiester backbone structures on binding and repair of pyrimidine dimers by Escherichia coli DNA photolyase.

Photolyases reverse the effects of UV light on cells by converting cyclobutane dipyrimidine photoproducts (pyrimidine dimers, Pyr mean value of Pyr) into pyrimidine monomers in a light-dependent reaction. Previous work has suggested that, based on substrate preference, there are two classes of photolyase: DNA photolyase as exemplified by the Escherichia coli enzyme, and RNA photolyases found in plants such as Nicotiana tabacum and Phaseolus vulgaris. In experiments aimed at identifying substrate determinants, including the pentose ring, for binding and catalysis by E. coli DNA photolyase we tested several Pyr mean value of Pyr. We found that the enzyme has relative affinities for photodimers of T mean value of T greater than or equal to U mean value of T greater than U mean value of U much greater than C mean value of C and that the E-FADH2 form of the enzyme repairs these dimers at 366 nm with absolute quantum yields of 0.9 (T mean value of T), 0.8 (U mean value of T), 0.6 (U mean value of U), and 0.05 (C mean value of C). The enzyme also repairs an isolated thymine dimer and the synthetic substrate, 1,1'-trimethylene-bis (thymine) cyclobutane dimer. Unexpectedly, we found that this enzyme, previously thought to be specific for DNA, repairs uracil cyclobutane dimers in poly(rU). The affinity of photolyase for a uracil dimer in RNA is about 10(4)-fold lower than that for a U mean value of U in DNA; however, once bound, the enzyme repairs the photodimer with the same quantum yield whether the dimer is in ribonucleoside or deoxyribonucleoside form.

Base Composition↗
PubMed2000

High-resolution structure of the HNF-1alpha dimerization domain.

The N-terminal dimerization domain of the transcriptional activator hepatocyte nuclear factor-1alpha (HNF-1alpha) is essential for DNA binding and association of the transcriptional coactivator, DCoH (dimerization cofactor of HNF-1). To investigate the basis for dimerization of HNF-1 proteins, we determined the 1.2 A resolution X-ray crystal structure of the dimerization domain of HNF-1alpha (HNF-p1). Phasing was facilitated by devising a simple synthesis for Fmoc-selenomethionine and substituting leucine residues with selenomethionine. The HNF-1 dimerization domain forms a unique, four-helix bundle that is preserved with localized conformational shifts in the DCoH complex. In three different crystal forms, HNF-p1 displays subtle shifts in the conformation of the interhelix loop and the crossing angle between the amino- and carboxyl-terminal helices. In all three crystal forms, the HNF-p1 dimers pair through an exposed hydrophobic surface that also forms the binding site for DCoH. Conserved core residues in the dimerization domain of the homologous transcriptional regulator HNF-1beta rationalize the functional heterodimerization of the HNF-1alpha and HNF-1beta proteins. Mutations in HNF-1alpha are associated with maturity-onset diabetes of the young type 3 (MODY3), and the structure of HNF-p1 provides insights into the effects of three MODY3 mutations.

Amino Acid Motifs↗
PubMed2001

Dimeric procaspase-3 unfolds via a four-state equilibrium process.

We have examined the folding and assembly of a catalytically inactive mutant of procaspase-3, a homodimeric protein that belongs to the caspase family of proteases. The caspase family, and especially caspase-3, is integral to apoptosis. The equilibrium unfolding data demonstrate a plateau between 3 and 5 M urea, consistent with an apparent three-state unfolding process. However, the midpoint of the second transition as well as the amplitude of the plateau are dependent on the protein concentration. Overall, the data are well described by a four-state equilibrium model in which the native dimer undergoes an isomeration to a dimeric intermediate, and the dimeric intermediate dissociates to a monomeric intermediate, which then unfolds. By fitting the four-state model to the experimental data, we have determined the free energy change for the first step of unfolding to be 8.3 +/- 1.3 kcal/mol. The free energy change for the dissociation of the dimeric folding intermediate to two monomeric intermediates is 10.5 +/- 1 kcal/mol. The third step in the unfolding mechanism represents the complete unfolding of the monomeric intermediate, with a free energy change of 7.0 +/- 0.5 kcal/mol. These results show two important points. First, dimerization of procaspase-3 occurs as a result of the association of two monomeric folding intermediates, demonstrating that procaspase-3 dimerization is a folding event. Second, the stability of the dimer contributes significantly to the conformational free energy of the protein (18.8 of 25.8 kcal/mol).

Caspase 3↗
PubMed2003

Probing the dimeric structure of porcine aminoacylase 1 by mass spectrometric and modeling procedures.

Aminoacylase 1 is a zinc-binding metalloprotease catalyzing the hydrolysis of N(alpha)-acylated l-amino acids; it presents altered expression levels in different renal and small cell lung carcinomas. A description of its redox and oligomerization state was achieved by combined biochemical and mass spectrometric procedures. A topological analysis of the enzyme structural architecture was derived from limited proteolysis and selective chemical modification experiments, using a broad range of proteases and chemical reagents. The analysis of the reaction products by different mass spectrometric techniques identified 26 amino acids as being accessible on the molecular surface, defining polypeptide regions exposed in the structure of the dimeric protein. The nature of the intermolecular contact zone between monomers was investigated by cross-linking reaction and mass mapping experiments. The cross-linked dimer was isolated, and the intermolecular cross-linked peptides were characterized, thus demonstrating the spatial proximity of Lys220 and Lys231 at the dimerization interface. Standard modeling procedures based on automatic alignment on the structure of members of the M20 peptidase family failed to produce a dimeric model consistent with experimental data. Discrepancies were observed mainly at the dimer interface and at loop regions. Therefore, a refined model for this dimeric protease was calculated by selecting the one able to generate a structure fully compatible with experimental findings, among all possible suboptimal sequence alignments. According to this model, each aminoacylase monomer consists of two domains: a globular catalytic subunit (residues 1-188 and 311-399) consisting of a beta-sheet sandwiched between alpha-helices and a second beta-sheet located on the surface, and the dimerization domain (residues 189-310) folding into a beta-sheet flanked on one side by two alpha-helices. These results indicate that reliable approaches such as limited proteolysis, selective chemical modification, and cross-linking coupled to mass spectrometry can be used to test and optimize molecular models of multimeric proteins and highlight problems in automatic model building.

Amidohydrolases↗
PubMed2002

The effect of salts on the stability of the H2A-H2B histone dimer.

The core nucleosome, which comprises an H3-H4 tetramer and two H2A-H2B dimers, is not a static DNA packaging structure. The nucleosome is a dynamic protein-DNA complex, and the modulation of its structure is an important component of transcriptional regulation. To begin to understand the molecular details of nucleosome dynamics, we have investigated the stability of the isolated H2A-H2B dimer. The urea-induced equilibrium responses of the heterodimer have been examined by far-UV circular dichroism and intrinsic tyrosine fluorescence. The two spectroscopic probes yielded coincident transitions, and global fitting of the reversible urea-induced unfolding further demonstrated that H2A-H2B unfolds by a two-state equilibrium response. At physiological ionic strengths, the free energy of unfolding in the absence of urea of H2A-H2B is 11.8 +/- 0.3 kcal mol(-)(1), moderate stability for a dimer of 26.4 kDa. The m value, or sensitivity of the unfolding to urea, is 2.9 +/- 0.1 kcal mol(-)(1) M(-)(1). This value is significantly larger than would be predicted for the unfolding of the dimerization motif alone ( approximately 2 kcal mol(-)(1) M(-)(1)), suggesting that the N-terminal tails may adopt a collapsed, solvent-excluding structure that undergoes an unfolding transition. The efficacies of several potassium salts and three chloride salts to stabilize the H2A-H2B dimer were determined. The salt-dependent stabilization of the H2A-H2B dimer shows that the Hofmeister effect is the predominant mode of stabilization. However, studies employing multiple salts suggest that there is a component of stabilization that must arise from screening of electrostatic repulsion in the highly basic heterodimer. The most highly charged regions of the dimer are the N-terminal tails, sites of posttranslational modifications such as acetylation and phosphorylation. These modifications, which alter the charge density of the tails, are involved in regulation of nucleosome dynamics.

Ammonium Chloride↗