PDB:2IO5

Protein Name

CIA-histone H3-H4 complex

Species

Homo sapiens (human)

Biological Context

Histones are used for packing DNA and comprise nucleosome, the fundamental unit of chromosome, with DNA. A nucleosome consists of a histone octamer build from two histone H2A-H2B dimers and a histone H3-H4 tetramer, with surrounding DNA(xPSSS:1AOI). Because histone modification such as acetylation and methylation affects gene expression pattern, histone itself is also an important genetic resource from the epigenetic perspective.

It is reported that CIA/ASF1 mediates nucleosome assembly by forming a complex with another histone chaperone in human cells and yeast, and is involved in DNA replication, transcription, DNA repair and silencing/anti-silencing in yeast. The CIA-histone-H3-H4 complex was isolated from Drosophila as a histone chaperone CAF-1 stimulator. Histone chaperons have various roles as above, and still their detail function remains unknown. Nevertheless, histone chaperons are believed to be essential for nucleosome assembly and disassembly.

This crystal structure of the CIA/ASF1-histone-H3-H4 complex (Fig. 1) revealed an intermediate structure of the nucleosome replication. CIA/ASF1 has a histone H3-H4 tetramer-disrupting activity, which is required to form the CIA/ASF1-histone-H3-H4 complex from the histone H3-H4 tetramer (Fig. 2). Thus, it is suggested that, during the replication process of chromosome, nucleosomes undergo its semi-conservative replication as DNA do (Fig. 3).

Structure Description

The crystal structure of human CIA-I in complex with Xenopus core histones H3 and H4 was determined at 2.7Å. Because human and Xenopus histones H3 and H4 differ by only one amino acid in total which is not located at the interacting surface of the complex, this structure can be regarded as a homologous system.

CIA-I contacts with both H3 and H4, and interestingly, to the contact surfaces of H3 and H4 also used for histone octamer formation. It is striking that the C-terminal β-strand of histone H4 changes its partner from the β-strand in histone H2A to that of CIA-I through a large conformational change. Besides, the structure shows the H3-H4 dimer’s mutually exclusive interactions with another histone H3-H4 dimer and CIA-I (Fig. 1, 2). This suggests that CIA-I has histone H3-H4 tetramer-disrupting activity to form the CIA-I-histone-H3-H4-complex. An in vitro functional analysis also demonstrated this CIA-I disrupting activity.

In contrast to the nucleosome disassembly activity, the nucleosome assembly activity of CIA should be carried out with other factors like histone-, CIA-interacting factors and DNA. Evaluation of the assembly mechanism and verification of the nucleosome semi-conservative replication are expected in the future.

	(Fig. 1) CIA-I-histone H3-H4 complex CIA-I, histone H3, and histone H4 are shown in red, blue, and orange, respectively. An α helix of H3 and a β strand of H4 contact with CIA.
	(Fig. 2) Histone H3-H4 tetramer This tetramer consists of two histone H3 (blue and light blue) and two histone H4 (orange and light orange) (xPSSS:1AOI). The H3 (light blue)-H4 (light orange) dimer overlaps the CIA on Fig.1.
	(Fig. 3) Histone H3-H4 tetramer replications model A replication model with CIA-bound histone H3-H4 dimers as intermediates. Because DNA and histone H2A-H2B can also divide into two, the whole nucleosome structure also could use the semi-conservative replication.

Protein Data Bank (PDB)

References

Source

Natsume, R. Eitoku, M. Akai, Y. Sano, N. Horikoshi, M. Senda, T.; "Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4"; Nature; (2007) 446:338-341 PubMed:17293877.

Others

UniProt:Q6IA08 UniProt:P84233 UniProt:P62799

author: Naoya Fujita

Japanese version:PDB:2IO5