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Commentary the Histone Fold: Evolutionary Questions V Proc. Natl. Acad. Sci. USA Vol. 92, pp. 11328-11330, December 1995 Commentary The histone fold: Evolutionary questions V. Ramakrishnan Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84132 While histones as a class of protein asso- of each dimer pair had been suggested by central helix in the histone fold arose as a ciated with DNA have been known for NMR studies (7, 8). result of a fusion between helices from over a hundred years, our current ideas of In a recent issue of the Proceedings (9), each HSH motif. Since the basic structural how histones associate with DNA began Arents and Moudrianakis use the struc- unit is half a fold, this lends support to the with the discovery of the nucleosome as a ture of the core histones to investigate the idea of a gene-doubling in the histones, basic structural unit of chromatin (1, 2). In chemical and structural nature of the his- although it is clearly present in all the the nucleosome, two left-handed super- tone fold and offer arguments for a com- histones and not just H2A as suggested by helical turns of DNA wrap around an mon origin for the core histones. In a sequence comparison studies. Moreover, octameric histone core consisting of two related paper (10), it is shown that the this suggests that the gene-doubling event copies of each of the four core histones- histone fold occurs in a variety of different occurred before the differentiation of the H2A, H2B, H3, and H4. proteins. Taken together, these results core histones into the four types. Arents The publication by Moudrianakis and show that the fold forms the basis for a and Moudrianakis (9) have now made coworkers of the crystal structure of the distinct family of proteins. quantitative comparisons of the degree of histone octamer (3) was a landmark in the Each of the core histones is highly con- structural similarity between the histone field of chromatin. An immediate reason served (11, 12). Histones H3 and H4 are folds of the four core histones. These was that the crystal structure was in good among the most highly conserved proteins comparisons show that the fold is quite agreement with previous electron-micro- known, both in sequence and in length. similar in the four histones. If the N- scopic studies on the octamer (4), as well Histones H2A and H2B have regions that terminal and C-terminal halves of the as with the crystal structure of the nucleo- are more variable, especially at their ter- histone fold (or just the HSH motif) are some core particle at 7 A (5), thereby mini, but each has a highly conserved compared, the similarity is even greater, resolving an earlier controversy. The sur- core. However, the four core histones but this is not unexpected because the face of the octamer had a left-handed have little sequence similarity with respect motif being compared is twice as small helical ramp to which DNA presumably to one another, with pairwise identities and may have fewer degrees of freedom was bound in the nucleosome. When DNA that range from 15% to 20%. structurally. Apart from the structural was modeled onto this ramp, it agreed Despite the low sequence identity, a comparisons, other arguments are offered very well with the general features of the common origin for the core histones had for a common origin for the core histones. DNA observed in the nucleosome core been suggested by comparisons of the core Within each dimer, the fold portions of the particle (5). This showed that the structure histone amino acid sequences (13, 14). histones are related by an approximate of the isolated octamer was likely to be These studies suggested that the core hi- two-fold axis (see Fig. 1). This suggests similar to its structure in the nucleosome, stones were related to one another, but that, although today the histone dimers thus establishing the relevance of the work not to the linker histone Hi. Further, both are heterotypic, the ancestral dimer may for chromatin. studies offered evidence that histone H2A have been a homodimer with a true two- However, the crystal structure of the had an internal repeat that suggested that fold axis. More importantly, the point is octamer was important for a more funda- it was the product of a gene doubling made that histone-like proteins in archae- mental reason: it was the first structure at event. However, a study that compared bacteria are more similar to each of the sufficient resolution to allow the tertiary gene sequences questioned the gene dou- core histones than any one of the core fold of the individual core histones to be bling of H2A (15), and there were some histones is to the others. determined, with some surprising results. inconsistencies in the conclusions of the It is not difficult to rationalize why each It has been known for a long time that three studies, perhaps because of the lim- core histone has been highly conserved. histones associate with one another in ited number of complete histone se- Each histone has to make numerous in- solution. The most stable interactions are quences available at the time as well as the teractions, including interactions with its those of the heterotypic dimers H2A-H2B low degree of sequence identity. Because dimer partner, with other components of and H3-H4 (6). The H3-H4 dimers fur- ofthese inconsistencies, these studies were the octamer, and with DNA, and is there- ther associate to form a stable (H3-H4)2 not regarded as definitive [see discussion by fore subject to a variety of selective pres- tetramer. The crystal structure of the oc- van Holde (16)]. Nevertheless, gene dou- sures. However, this in itself creates an- tamer shows that the histones are indeed bling in H2A was also suggested by van other puzzle. If the core histones de- associated as heterotypic dimers within Holde (16), who showed a sequence simi- scended from a common ancestor, it is the octamer and revealed the basis for this larity between the N-terminal region of the clear that they have diverged considerably dimerization: despite little sequence sim- archaebacterial DNA-binding protein HTa over time into the four types. If they were ilarity, all four histones share a common with both the N- and C-terminal domains of allowed to diverge in this manner, what structural motif, the histone fold, which is H2A. It now turns out that the basic con- slowed the divergence once the four core involved in dimerization with its partner. clusions of these sequence comparison stud- histones had differentiated? As shown in Fig. 1 for the H3-H4 dimer, ies, although incomplete, were right. Although arguments have been made each histone is highly elongated and clasps Subsequent analysis showed that the for why the core histones have their par- its partner in the dimer by means of ex- histone fold itself could be considered as ticular structure to facilitate the formation tensive interactions in what Arents et al. a repeat of a basic helix-strand-helix of the octamer and the nucleosome (3), it (3) term a "handshake motif." Such ex- (HSH) motif that occurred in both halves is not clear that four different subtypes are tensive interactions between the members of the fold (17); this suggests that the long needed to form nucleosome-like struc- 11328 Downloaded by guest on September 24, 2021 Commentary: Ramakrishnan Proc. Natl. Acad. Sci. USA 92 (1995) 11329 FIG. 1. Stereo ribbon diagram showing the involvement of the histone fold in the formation of the H3-H4 dimer present in the histone octamer (3), with the C termini of the chains marked for identification. The helix-strand-helix (HSH) motif that forms each half of the fold is present in all four core histones, and the long central helix can be considered the result of the fusion of two helices, one from each half. The H2A-H2B dimer has a similar structure. (Figure courtesy of E. N. Moudrianakis.) tures containing superhelical DNA. In of H3 or H4. Histones H2A and H2B may the family are elucidated, the diversity of bacteria, the histone-like protein HU can have been later players, whose role is roles played by the fold will become clear. supercoil DNA to form beaded structures further condensation of nucleosomal Apart from identifying evolutionary re- that are reminiscent of nucleosomes (18). DNA as well as modulation of transcrip- lationships, the structure of the octamer The three-dimensional structure of HU (19) tion, and they may have diverged as these provides the basis to answer several bio- suggests how a single protein could self- roles, especially the latter, changed over chemical questions. Each of the core his- associate and bend DNA around itself evolution. In the absence of other proteins tones has some tendency to self-associate In today's nucleosome, the roles of the that are homologous to the histones, such (6), but the specific dimers (H2A-H2B) (H3-H4)2 tetramer and the H2A-H2B evolutionary hypotheses are difficult to and H3-H4) form with higher affinity dimers are very different. The tetramer is test. Interestingly, two such proteins have than either homodimers or other hetero- thought to be the first to associate with been identified recently: the centromere- typic combinations. What is the chemical DNA; it organizes the central 120 bp of associated proteins CSE4 and CENP-A basis of this specificity? And what is the nucleosomal DNA (20) and is known to both have a high degree of homology with chemical basis for the specific stabilization determine nucleosome positioning (21).
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