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Structure of the quaternary complex of histone H3-H4 heterodimer with chaperone ASF1 and the replicative helicase subunit MCM2.

Wang H, Wang M, Yang N, Xu RM - Protein Cell (2015)

View Article: PubMed Central - PubMed

Affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.

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The building block of eukaryotic chromatin is the nucleosome core particle (NCP), which is consisted of ~146 bps of DNA wrapped around an octamer of core histones... A tetramer of histone H3 and H4 and two H2A-H2B dimers form the histone octamer (Kornberg, ; Luger et al., ; Thomas and Kornberg, )... During DNA replication, nucleosome disassembly and reassembly occurs at the replication fork, and histone chaperons CAF-1 and ASF1 are principally responsible for the deposition of histones H3 and H4 onto replicated DNA (Kaufman et al., ; Tyler et al., )... The projection of the C-terminal segment of ASF1 is largely determined by the position of the immediately N-terminal strand β9, which is stabilized by antiparallel pairing with the C-terminal β-strand (βC) of histone H4 (Fig.  1B)... It is interesting to note that while βC is positioned similarly in our quaternary complex and the ASF1-H3-H4 ternary complex, it contrasts sharply with that found in the (MCM2-H3-H4)2 complex (Fig.  1E)... Superposition of our structure with the NCP structure (PDB code: 2CV5, shows in gray) via the H3-H4 heterodimer shows that (1) ASF1 occupies a position blocking the dimerization interface of histone H3, thus preventing the formation of a (H3-H4)2 tetramer (Fig.  2A, Region 1); (2) MCM2 occludes the binding of histone H2B to histone H4 through its α2 helix, which impedes the association of H2A-H2B heterodimers with (H3-H4)2 tetramer to form an octamer (Fig.  2A, Region 2); (3) both the binding of MCM2 to the positively charged surface of the H3-H4 heterodimer and the protrusion of the C-terminal α2 helix of ASF1 would obstruct the wrapping of DNA in NCP... Exactly how ASF1 is recruited to the replication or damage foci remains poorly understood, except that ASF1 is known to directly interact with the CAF-1 complex (Mello et al., )... A recent result also showed the association of MCM complex with ASF1 in U2OS cells (Drissi et al., )... A summary of possible cellular functions of the interactions among MCM2, ASF1 and histones H3 and H4 is depicted in Fig.  2B, and the structural basis for their interactions learned here should help the dissection of their functions in chromatin biology... N.Y. is also supported by the Youth Innovation Promotion Association of CAS... All authors declare that they have no conflict of interest... This article does not contain any studies with human or animal subjects performed by any of the authors... Supplementary material 1 (PDF 249 kb)

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Possible biological functions of the MCM2-ASF1-H3-H4 complex. (A) The binding of MCM2 and ASF1 obstructs the formation of NCP and a histone (H3-H4)2 tetramer. A human nucleosome structure (PDB code: 2CV5, shown in gray) is aligned with the MCM2-ASF1-H3-H4 structure via the H3-H4 heterodimer. Four obstructed regions are enclosed in red circles and numbered according to the order in which they were referenced in the text. (B) A model of possible biological functions of the MCM2-ASF1-H3-H4 quaternary complex in the cytoplasm and in the nucleus. The cytosolic MCM2 may facilitate nuclear import of histones H3 and H4. In the nucleus, ASF1 “hands” the H3-H4 heterodimer to the CAF-1 complex prior to the deposition onto replicated DNA, in the presence or absence of MCM2. The ASF1-H3-H4 complex might also be directly recruited to the replication fork by interaction with the MCM complex
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Fig2: Possible biological functions of the MCM2-ASF1-H3-H4 complex. (A) The binding of MCM2 and ASF1 obstructs the formation of NCP and a histone (H3-H4)2 tetramer. A human nucleosome structure (PDB code: 2CV5, shown in gray) is aligned with the MCM2-ASF1-H3-H4 structure via the H3-H4 heterodimer. Four obstructed regions are enclosed in red circles and numbered according to the order in which they were referenced in the text. (B) A model of possible biological functions of the MCM2-ASF1-H3-H4 quaternary complex in the cytoplasm and in the nucleus. The cytosolic MCM2 may facilitate nuclear import of histones H3 and H4. In the nucleus, ASF1 “hands” the H3-H4 heterodimer to the CAF-1 complex prior to the deposition onto replicated DNA, in the presence or absence of MCM2. The ASF1-H3-H4 complex might also be directly recruited to the replication fork by interaction with the MCM complex

Mentions: The principal functions of histone chaperones are to keep the histones in their pre-depositional, DNA-free state. Superposition of our structure with the NCP structure (PDB code: 2CV5, shows in gray) via the H3-H4 heterodimer shows that (1) ASF1 occupies a position blocking the dimerization interface of histone H3, thus preventing the formation of a (H3-H4)2 tetramer (Fig. 2A, Region 1); (2) MCM2 occludes the binding of histone H2B to histone H4 through its α2 helix, which impedes the association of H2A-H2B heterodimers with (H3-H4)2 tetramer to form an octamer (Fig. 2A, Region 2); (3) both the binding of MCM2 to the positively charged surface of the H3-H4 heterodimer and the protrusion of the C-terminal α2 helix of ASF1 would obstruct the wrapping of DNA in NCP. These features of MCM2 and ASF1 define them as bona fide histone H3-H4 chaperones.Figure 2


Structure of the quaternary complex of histone H3-H4 heterodimer with chaperone ASF1 and the replicative helicase subunit MCM2.

Wang H, Wang M, Yang N, Xu RM - Protein Cell (2015)

Possible biological functions of the MCM2-ASF1-H3-H4 complex. (A) The binding of MCM2 and ASF1 obstructs the formation of NCP and a histone (H3-H4)2 tetramer. A human nucleosome structure (PDB code: 2CV5, shown in gray) is aligned with the MCM2-ASF1-H3-H4 structure via the H3-H4 heterodimer. Four obstructed regions are enclosed in red circles and numbered according to the order in which they were referenced in the text. (B) A model of possible biological functions of the MCM2-ASF1-H3-H4 quaternary complex in the cytoplasm and in the nucleus. The cytosolic MCM2 may facilitate nuclear import of histones H3 and H4. In the nucleus, ASF1 “hands” the H3-H4 heterodimer to the CAF-1 complex prior to the deposition onto replicated DNA, in the presence or absence of MCM2. The ASF1-H3-H4 complex might also be directly recruited to the replication fork by interaction with the MCM complex
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4537477&req=5

Fig2: Possible biological functions of the MCM2-ASF1-H3-H4 complex. (A) The binding of MCM2 and ASF1 obstructs the formation of NCP and a histone (H3-H4)2 tetramer. A human nucleosome structure (PDB code: 2CV5, shown in gray) is aligned with the MCM2-ASF1-H3-H4 structure via the H3-H4 heterodimer. Four obstructed regions are enclosed in red circles and numbered according to the order in which they were referenced in the text. (B) A model of possible biological functions of the MCM2-ASF1-H3-H4 quaternary complex in the cytoplasm and in the nucleus. The cytosolic MCM2 may facilitate nuclear import of histones H3 and H4. In the nucleus, ASF1 “hands” the H3-H4 heterodimer to the CAF-1 complex prior to the deposition onto replicated DNA, in the presence or absence of MCM2. The ASF1-H3-H4 complex might also be directly recruited to the replication fork by interaction with the MCM complex
Mentions: The principal functions of histone chaperones are to keep the histones in their pre-depositional, DNA-free state. Superposition of our structure with the NCP structure (PDB code: 2CV5, shows in gray) via the H3-H4 heterodimer shows that (1) ASF1 occupies a position blocking the dimerization interface of histone H3, thus preventing the formation of a (H3-H4)2 tetramer (Fig. 2A, Region 1); (2) MCM2 occludes the binding of histone H2B to histone H4 through its α2 helix, which impedes the association of H2A-H2B heterodimers with (H3-H4)2 tetramer to form an octamer (Fig. 2A, Region 2); (3) both the binding of MCM2 to the positively charged surface of the H3-H4 heterodimer and the protrusion of the C-terminal α2 helix of ASF1 would obstruct the wrapping of DNA in NCP. These features of MCM2 and ASF1 define them as bona fide histone H3-H4 chaperones.Figure 2

View Article: PubMed Central - PubMed

Affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The building block of eukaryotic chromatin is the nucleosome core particle (NCP), which is consisted of ~146 bps of DNA wrapped around an octamer of core histones... A tetramer of histone H3 and H4 and two H2A-H2B dimers form the histone octamer (Kornberg, ; Luger et al., ; Thomas and Kornberg, )... During DNA replication, nucleosome disassembly and reassembly occurs at the replication fork, and histone chaperons CAF-1 and ASF1 are principally responsible for the deposition of histones H3 and H4 onto replicated DNA (Kaufman et al., ; Tyler et al., )... The projection of the C-terminal segment of ASF1 is largely determined by the position of the immediately N-terminal strand β9, which is stabilized by antiparallel pairing with the C-terminal β-strand (βC) of histone H4 (Fig.  1B)... It is interesting to note that while βC is positioned similarly in our quaternary complex and the ASF1-H3-H4 ternary complex, it contrasts sharply with that found in the (MCM2-H3-H4)2 complex (Fig.  1E)... Superposition of our structure with the NCP structure (PDB code: 2CV5, shows in gray) via the H3-H4 heterodimer shows that (1) ASF1 occupies a position blocking the dimerization interface of histone H3, thus preventing the formation of a (H3-H4)2 tetramer (Fig.  2A, Region 1); (2) MCM2 occludes the binding of histone H2B to histone H4 through its α2 helix, which impedes the association of H2A-H2B heterodimers with (H3-H4)2 tetramer to form an octamer (Fig.  2A, Region 2); (3) both the binding of MCM2 to the positively charged surface of the H3-H4 heterodimer and the protrusion of the C-terminal α2 helix of ASF1 would obstruct the wrapping of DNA in NCP... Exactly how ASF1 is recruited to the replication or damage foci remains poorly understood, except that ASF1 is known to directly interact with the CAF-1 complex (Mello et al., )... A recent result also showed the association of MCM complex with ASF1 in U2OS cells (Drissi et al., )... A summary of possible cellular functions of the interactions among MCM2, ASF1 and histones H3 and H4 is depicted in Fig.  2B, and the structural basis for their interactions learned here should help the dissection of their functions in chromatin biology... N.Y. is also supported by the Youth Innovation Promotion Association of CAS... All authors declare that they have no conflict of interest... This article does not contain any studies with human or animal subjects performed by any of the authors... Supplementary material 1 (PDF 249 kb)

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Related in: MedlinePlus