Histones histone-fold

Figure 1. Variants of the histones H3 from yeast Saccharomyces cerevisiae S.c.), fruit fly Drosophila melanogaster D.m), and human Homo sapiens H.s.). H3.1 is identical to H3.2 with the exception of a serine to cysteine exchange (top). H3.3 differs from H3.1/H3.2 only in four amino acid positions. Centromer-specific histones (CenH3 s) have an amino terminus of variable length (between 20 and 200 residues). They also possess an extended loop 1 region in the histone fold domain...

On the other hand, recognition of the histone fold in archaeal chromatin and its implications for the formation of nucleosome-like structures, has provided important insights into the probable evolution of the eukaryotic chromatin [62],... 

Although the histone fold was first described from the structure of the histone octamer core of the nucleosome [17], the high a-helical content was predicted much earlier [43]. The core histones possess three functional domains (1) the histone fold domain, (2) an N-terminal tail domain, and (3) various accessory helices and less structured regions. The N-terminal tail domains of the core histones are currently the focus of intense research. Covalent modifications of residues in these unstructured domains appear to modify local chromatin structure, either directly or... 

Fig. 7. Ribbon Ca model of H4 showing the folding pattern of an exemplar histone. The canonical histone fold includes one long medial a-helix (mH) with two shorter a-helices towards the N- and C-termini (NH, CH), bound by loops (NL, CL) to the primary helix.

The histone fold appears as a symmetrical duplication of a helix-fold-helix motif [18,19] with a long median helix, the mH helix, and two shorter terminal helices, the N-terminal or NH helix and the C-terminal or CH helix (Fig. 7). The helices are joined by loops N-terminal, the NL loop, and C-terminal, the CL loop, to the mH helix. The formation of heterodimer pairs is accomplished through a handshake [17] pairing in which the mH helices of the handshake partners align in opposite orientations such that the NL loop of one partner aligns in a parallel orientation with the CL loop of the other (Fig. 8). 

Despite many biochemical similarities between linker and core histones the proteins of these two groups differ in architecture, evolutionary origin, and function. Each of the four core histones has a characteristic histone fold domain. The latter is an old and ubiquitous structural motif used in DNA compaction and protein dimerization [3]. Linker histones do not have a histone fold. The canonical... 

Sullivan, K.F., Hechenberger, M., and Masri, K. (1994) Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere. J. Cell Biol. 127, 581-592. Choo, K.H. (2000) Centromerization. Trends Cell Biol. 10, 182-188. 

Chen, Y., Baker, R.E., Keith, K.C., Harris, K., Stoler, S., and Fitzgerald-Hayes, M. (2000) The N terminus of the centromere H3-like protein Cse4p performs an essential function distinct from that of the histone fold domain. Mol. Cell. Biol. 20, 7037-7048. 

From a structural perspective, histones can be considered to consist of a tri-partite organization in which a central histone fold domain [81] is flanked by N- and C-terminal regions tails with a low level of folding. The histone fold is responsible for the histone bundle and handshake interactions that hold the histone octamer together [45,265,307,308] while the tails do not appear to have any major role in the stability of the octamer subunits [309]. 

From all the above it would be expected that only histone variability (variants or post-translational modification) affecting the histone fold or C-terminal domains would have a major effect on nucleosome stability in agreement with the experimental results that will be described in the following sections. 

Nucleosome arrays reconstituted from 208-18 and either histone octamers, H3/H4 tetra-mers or the histone-fold protein HMf from... 

Pool, R.A., Dellaire, G., Hulsmann, B.B., Grimaldi, M.A., Corona, D.F., Becker, P.B., Bickmore, W.A., and Varga-Weisz, P.D. (2000) HuCHRAC, a human ISWI chromatin remodeling complex contains hACFl and two novel histone-fold proteins. EMBO J. 19, 3377-3387. 

Corona, D.F., Eberharter, A., Budde, A., Deuring, R., Ferrari, S., Varga-Weisz, P., Wilm, M., Tamkun, J., and Becker, P.B. (2000) Two histone fold proteins, CHRAC-14 and CHRAC-16, are developmentally regulated subunits of chromatin accessibility complex (CHRAC). EMBO J. 19, 3049-3059. 

All of the core histones share a conserved 65-residue histone fold.27 28 The arginine-rich histones have a strongly conserved amino acid sequence, histone H4 from pea seedlings differing from that of the bovine thymus by only two amino acids. On the other hand, the lysine-rich HI is almost species-specific in its sequence. Differentiated tissues contain at least seven variant forms of histone HI including proteins designated HI0, Hit, and H5 29-31... 

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