Mohideen K et al. (2010), Perturbations in nucleosome structure from heav...

XB-ART-42299

Nucleic Acids Res 2010 Oct 01;3818:6301-11. doi: 10.1093/nar/gkq420.

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Perturbations in nucleosome structure from heavy metal association.

Mohideen K , Muhammad R , Davey CA .

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Heavy metals have the potential to engage in strong bonding interactions and can thus function in essential as well as toxic or therapeutic capacities. We conducted crystallographic analyses of heavy cation binding to the nucleosome core particle and found that Co(2+) and Ni(2+) preferentially associate with the DNA major groove, in a sequence- and conformation-dependent manner. Conversely, Rb(+) and Cs(+) are found to bind only opportunistically to minor groove elements of the DNA, in particular at narrow AT dinucleotide sites. Furthermore, relative to Mn(2+) the aggressive coordination of Co(2+) and Ni(2+) to guanine bases is observed to induce a shift in histone-DNA register around the nucleosome center by stabilizing DNA stretching over one region accompanied by expulsion of two bases at an opposing location. These 'softer' transition metals also associate with multiple histone protein sites, including inter-nucleosomal cross-linking, and display a proclivity for coordination to histidine. Sustained binding and the ability to induce structural perturbations at specific locations in the nucleosome may contribute to genetic and epigenetic mechanisms of carcinogenesis mediated by Co(2+) and Ni(2+).

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Species referenced: Xenopus laevis
Genes referenced: h2ac21 h2bc21

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	Figure 1. The presence of Co2+ or Ni2+ induces a shift in histone–DNA register and distortions in the double helix. (A) The Ni2+-NCP structure viewed along the particle pseudo 2-fold axis (small arrow). The 47 Ni2+ ions appear as magenta spheres, the two DNA strands are orange and cyan and histone proteins are shown in blue (H3), green (H4), yellow (H2A) and red (H2B). Ni2+ or Co2+ association causes displacement of a bp from one particle half to the opposing half (curved arrow; bracket indicates location of base flip-out distortion). This is also apparent from asymmetry in metal binding about the dyad axis. (B) Minor and major groove-inward sections of NCP147 are orange and black, respectively. The base or nucleotide numbering scheme (b/n) is relative to Mn2+-NCP (top) and corresponds to the 5′ (−) to 3′ (+) direction of either DNA strand in the duplex (SHL = superhelix location, turns from center). A gap in the sequence represents a shift in histone-bp register from DNA stretching (approximate expanse of distortion, magenta lines), which is accompanied by base expulsion at the 1.5-turn location in Co2+-NCP and Ni2+-NCP. Green dots represent two strong peaks in the anomalous difference map that correspond to Co2+/Ni2+-guanine coordination in the refined model (bottom), whereas they coincide with inappropriate binding sites in the Mn2+-NCP model (top).
	Figure 2. Co2+ or Ni2+ binding promotes base expulsion from the double helical stack at the 1.5-turn location. (A and B) Co2+-NCP (A) and Ni2+-NCP (B) display flipping out of cytosine 15 and guanine −16 (arrows). An Fo−Fc electron density map (2.5σ), in which ATGCCTT/AAGGCAT nucleotides ±12 to ±18 were omitted from the respective models, is displayed superimposed on the structures. (C) Heavy divalent metal binding appears to directly promote the double helix deformation. Co2+ (magenta sphere) is observed to coordinate to the N7 atom of guanine 14, which is situated in the ‘minor groove’ by virtue of assuming the syn glycosidic conformation. An anomalous difference electron density map (3.5σ) is shown superimposed on the Co2+-NCP model.
	Figure 3. Co2+/Ni2+-DNA binding site selectivity. (A and B) Ni2+ (A) and Co2+ (B) binding to GG dinucleotide sites at locations 61 and −35/−34, respectively. Displacement of the 3′ guanine into the major groove at position −34 (arrow) allows N7/O6 cross-linking and creates a secondary, low occupancy, site for N7 coordination to the 3′ base. An anomalous difference electron density map, contoured at 8σ (A) and 4σ (B), is shown superimposed on the model. (C and D) The guanine base atoms at locations 8 (C) or 14 (D) from the Ni2+-NCP structure (gold carbon atoms) were least-squares superimposed onto those of the Mn2+-NCP structure (green) to illustrate how conformational alterations associated DNA stretching and histone–DNA register shifting can influence metal binding. In both instances, Co2+/Ni2+ binding occurs in the stretched particle half, whereas Mn2+ association is not observed at the respective locations. This appears to be largely a consequence of steric clearance provided by positive slide at the TG elements (arrow) associated with the change in DNA orientation. (A–D) Co2+/Ni2+ ions and coordinate (-covalent) bonds appear as magenta spheres and lines, respectively.
	Figure 4. Guanine–guanine overlap in GG=CC and GC dinucleotides influences divalent metal association (13,14). Simplified representation of the electrostatic potential around bases in GG and GC steps, adapted from ref. 42. The extensive electronegative zone (red) associated with the N7 and O6 atoms of guanine creates a general hotspot for cation association to the major groove. Bp step slide in the positive direction has opposite effects in GG versus GC steps, whereby guanine-guanine overlap is decreased and increased, respectively. The greater charge density for GG steps lacking large positive slide and GC steps having positive slide appears to promote divalent metal binding (green dumbbells).
	Figure 5. Co2+/Ni2+-histone binding site selectivity. (A) Co2+-aspartate coordination within an electronegative patch of H2A. (B) Ni2+ coordination to histidine, glutamate and an additional histidine ligand from the H4 tail of a neighboring particle (gray carbon atoms). (A and B) Co2+/Ni2+ ions and coordinate (-covalent) bonds appear as magenta spheres and lines, respectively. An anomalous difference electron density map, contoured at 4σ (A) and 8σ (B), is shown superimposed on the model.
	Figure 6. Cs+/Rb+ binding site selectivity. (A) Rb+ coordination in the minor groove at an AT dinucleotide element. (B) Cs+ coordination at an α-helix C-terminus. (A,B) Cs+/Rb+ ions and coordinate bonds appear as magenta spheres and broken lines, respectively. An anomalous difference electron density map, contoured at 4σ (A) and 5σ (B), is shown superimposed on the model.

References [+] :

Arita, Epigenetics in metal carcinogenesis: nickel, arsenic, chromium and cadmium. 2009, Pubmed