In addition to its histone fold, each of the core histones has an N-terminal amino acid “tail,” which extends out from the DNA–histone core (see Figure 4–24D). These histone tails are subject to several different types of covalent modifications that in turn control critical aspects of chromatin structure and function, as we shall discuss shortly.
As a reflection of their fundamental role in DNA function through controlling chromatin structure, the histones are among the most highly conserved eukaryotic proteins. For example, the amino acid sequence of histone H4 from a pea differs from that of a cow at only 2 of the 102 positions. This strong evolutionary conservation suggests that the functions of histones involve nearly all of their amino acids, so that a change in any position is deleterious to the cell. But in addition to this remarkable conservation, eukaryotic organisms also produce smaller amounts of specialized variant core histones that differ in amino acid sequence from the main ones. As discussed later, these variants, combined with the surprisingly large number of covalent modifications that can be added to the histones in nucleosomes, give rise to a variety of chromatin structures in cells.
Nucleosomes Have a Dynamic Structure, and Are Frequently Subjected to Changes Catalyzed by ATP-Dependent Chromatin Remodeling Complexes
For many years biologists thought that, once formed in a particular position on DNA, a nucleosome would remain fixed in place because of the very tight association between its core histones and DNA. If true, this would pose problems for genetic readout mechanisms, which in principle require easy access to many specific DNA sequences. It would also hinder the rapid passage of the DNA transcription and replication machinery through chromatin. But kinetic experiments show that the DNA in an isolated nucleosome unwraps from each end at a rate of about four times per second, remaining exposed for 10 to 50 milliseconds before the partially unwrapped structure recloses. Thus, most of the DNA in an isolated nucleosome is in principle available for binding other proteins.
For the chromatin in a cell, a further loosening of DNA–histone contacts is clearly required, because eukaryotic cells contain a large variety of ATP-dependent chromatin remodeling complexes. These complexes include a subunit that hydrolyzes ATP (an ATPase evolutionarily related to the DNA helicases discussed in Chapter 5). This subunit binds both to the protein core of the nucleosome and to the double-stranded DNA that winds around it. By using the energy of ATP hydrolysis to move this DNA relative to the core, the protein complex changes the structure of a nucleosome temporarily, making the DNA less tightly bound to the histone core. Through repeated cycles of ATP hydrolysis that pull the nucleosome core along the DNA double helix, the remodeling complexes can catalyze nucleosome sliding. In this way, they can reposition nucleosomes to expose specific regions of DNA, thereby making them available to other proteins in the cell (Figure 4–26). In addition, by cooperating with a variety of other proteins that bind to histones and serve as histone chaperones, some remodeling complexes are able to remove either all or part of the nucleosome core from a nucleosome—catalyzing either an exchange of its H2A–H2B histones, or the complete removal of the octameric core from the DNA (Figure 4–27). As a result of such processes, measurements reveal that a typical nucleosome is replaced on the DNA every one or two hours inside the cell.
DNA of nucleosome histone core of nucleosome (histone octamer) AA, TT, and TA dinucleotides preferred here (minor groove inside) (minor groove outside)
Figure 4–25 The bending of DNA in a nucleosome. The DNA helix makes 1.7 tight turns around the histone octamer. This diagram illustrates how the minor groove is compressed on the inside of the turn. Owing to structural features of the DNA molecule, the indicated dinucleotides are preferentially accommodated in such a narrow minor groove, which helps to explain why certain DNA sequences will bind more tightly than others to the nucleosome core.