1zr5

Crystal structure of the macro-domain of human core histone variant macroH2A1.2Crystal structure of the macro-domain of human core histone variant macroH2A1.2

Structural highlights

1zr5 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.92Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

H2AY_HUMAN Variant histone H2A which replaces conventional H2A in a subset of nucleosomes where it represses transcription. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Involved in stable X chromosome inactivation. Inhibits the binding of transcription factors and interferes with the activity of remodeling SWI/SNF complexes. Inhibits histone acetylation by EP300 and recruits class I HDACs, which induces a hypoacetylated state of chromatin. In addition, isoform 1, but not isoform 2, binds ADP-ribose and O-acetyl-ADP-ribose, and may be involved in ADP-ribose-mediated chromatin modulation.^[1] ^[2] ^[3] ^[4] ^[5]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Histone macroH2A is a hallmark of mammalian heterochromatin. Here we show that human macroH2A1.1 binds the SirT1-metabolite O-acetyl-ADP-ribose (OAADPR) through its macro domain. The 1.6-A crystal structure and mutants reveal how the metabolite is recognized. Mutually exclusive exon use in the gene H2AFY produces macroH2A1.2, whose tissue distribution differs. MacroH2A1.2 shows only subtle structural changes but cannot bind nucleotides. Alternative splicing may thus regulate the binding of nicotinamide adenine dinucleotide (NAD) metabolites to chromatin.

Splicing regulates NAD metabolite binding to histone macroH2A.,Kustatscher G, Hothorn M, Pugieux C, Scheffzek K, Ladurner AG Nat Struct Mol Biol. 2005 Jul;12(7):624-5. Epub 2005 Jun 19. PMID:15965484^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Angelov D, Molla A, Perche PY, Hans F, Cote J, Khochbin S, Bouvet P, Dimitrov S. The histone variant macroH2A interferes with transcription factor binding and SWI/SNF nucleosome remodeling. Mol Cell. 2003 Apr;11(4):1033-41. PMID:12718888
↑ Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, Pehrson JR, Berger JM, Kaufman PD, Adams PD. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell. 2005 Jan;8(1):19-30. PMID:15621527 doi:S1534580704004083
↑ Hernandez-Munoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E, Nusinow DA, Panning B, Marahrens Y, van Lohuizen M. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40. Epub 2005 May 16. PMID:15897469 doi:0408918102
↑ Doyen CM, An W, Angelov D, Bondarenko V, Mietton F, Studitsky VM, Hamiche A, Roeder RG, Bouvet P, Dimitrov S. Mechanism of polymerase II transcription repression by the histone variant macroH2A. Mol Cell Biol. 2006 Feb;26(3):1156-64. PMID:16428466 doi:10.1128/MCB.26.3.1156-1164.2006
↑ Chakravarthy S, Gundimella SK, Caron C, Perche PY, Pehrson JR, Khochbin S, Luger K. Structural characterization of the histone variant macroH2A. Mol Cell Biol. 2005 Sep;25(17):7616-24. PMID:16107708 doi:http://dx.doi.org/25/17/7616
↑ Kustatscher G, Hothorn M, Pugieux C, Scheffzek K, Ladurner AG. Splicing regulates NAD metabolite binding to histone macroH2A. Nat Struct Mol Biol. 2005 Jul;12(7):624-5. Epub 2005 Jun 19. PMID:15965484 doi:http://dx.doi.org/10.1038/nsmb956

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OCA

[1] Angelov D, Molla A, Perche PY, Hans F, Cote J, Khochbin S, Bouvet P, Dimitrov S. The histone variant macroH2A interferes with transcription factor binding and SWI/SNF nucleosome remodeling. Mol Cell. 2003 Apr;11(4):1033-41. PMID:12718888

[2] Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, Pehrson JR, Berger JM, Kaufman PD, Adams PD. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell. 2005 Jan;8(1):19-30. PMID:15621527 doi:S1534580704004083

[3] Hernandez-Munoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E, Nusinow DA, Panning B, Marahrens Y, van Lohuizen M. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40. Epub 2005 May 16. PMID:15897469 doi:0408918102

[4] Doyen CM, An W, Angelov D, Bondarenko V, Mietton F, Studitsky VM, Hamiche A, Roeder RG, Bouvet P, Dimitrov S. Mechanism of polymerase II transcription repression by the histone variant macroH2A. Mol Cell Biol. 2006 Feb;26(3):1156-64. PMID:16428466 doi:10.1128/MCB.26.3.1156-1164.2006

[5] Chakravarthy S, Gundimella SK, Caron C, Perche PY, Pehrson JR, Khochbin S, Luger K. Structural characterization of the histone variant macroH2A. Mol Cell Biol. 2005 Sep;25(17):7616-24. PMID:16107708 doi:http://dx.doi.org/25/17/7616

[6] Kustatscher G, Hothorn M, Pugieux C, Scheffzek K, Ladurner AG. Splicing regulates NAD metabolite binding to histone macroH2A. Nat Struct Mol Biol. 2005 Jul;12(7):624-5. Epub 2005 Jun 19. PMID:15965484 doi:http://dx.doi.org/10.1038/nsmb956

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