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PMID: 16829959 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Histone H3 recognition and presentation by the WDR5 module of the MLL1 complex.

Nature structural & molecular biology ·Vol. 13 ·No. 8 ·2006-08-00 ·Pages 704-12

Ruthenburg AJ, Wang W, Graybosch DM, Li H, Allis CD, Patel DJ, Verdine GL

Abstract

WDR5 is a core component of SET1-family complexes that achieve transcriptional activation via methylation of histone H3 on Nzeta of Lys4 (H3K4). The role of WDR5 in the MLL1 complex has recently been described as specific recognition of dimethyl-K4 in the context of a histone H3 amino terminus; WDR5 is essential for vertebrate development, Hox gene activation and global H3K4 trimethylation. We report the high-resolution X-ray structures of WDR5 in the unliganded form and complexed with histone H3 peptides having unmodified and mono-, di- and trimethylated K4, which together provide the first comprehensive analysis of methylated histone recognition by the ubiquitous WD40-repeat fold. Contrary to predictions, the structures reveal that WDR5 does not read out the methylation state of K4 directly, but instead serves to present the K4 side chain for further methylation by SET1-family complexes.

MeSH Terms
Amino Acid Sequence Binding Sites Crystallography, X-Ray Heterotrimeric GTP-Binding Proteins/chemistry,metabolism Histone-Lysine N-Methyltransferase Histones/chemistry,metabolism Humans Intracellular Signaling Peptides and Proteins Methylation Models, Molecular Molecular Sequence Data Multiprotein Complexes Myeloid-Lymphoid Leukemia Protein/chemistry,metabolism Peptides/chemistry,metabolism Protein Conformation
Chemicals
Histones Intracellular Signaling Peptides and Proteins KMT2A protein, human Multiprotein Complexes Peptides WDR5 protein, human Myeloid-Lymphoid Leukemia Protein Histone-Lysine N-Methyltransferase Heterotrimeric GTP-Binding Proteins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Ruthenburg Alexander J
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Wang Wooikoon
Graybosch Daina M
Li Haitao
Allis C David
Patel Dinshaw J
Verdine Gregory L
References (50)
50 references, click to expand
  1. Nucleosomal DNA regulates the core-histone-binding subunit of the human Hat1 acetyltransferase.
    Curr Biol. 1998 Jan 15;8(2):96-108 PMID: 9427644
  2. Unsafe SETs: histone lysine methyltransferases and cancer.
    Trends Biochem Sci. 2002 Aug;27(8):396-402 PMID: 12151224
  3. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes.
    Acta Crystallogr D Biol Crystallogr. 2004 Aug;60(Pt 8):1355-63 PMID: 15272157
  4. MLL: a histone methyltransferase disrupted in leukemia.
    Trends Mol Med. 2004 Oct;10(10):500-7 PMID: 15464450
  5. Electrostatics of nanosystems: application to microtubules and the ribosome.
    Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10037-41 PMID: 11517324
  6. Catalytic mechanism and product specificity of the histone lysine methyltransferase SET7/9: an ab initio QM/MM-FE study with multiple initial structures.
    J Am Chem Soc. 2006 Feb 1;128(4):1272-8 PMID: 16433545
  7. Breaking good resolutions with ARP/wARP.
    J Synchrotron Radiat. 2004 Jan 1;11(Pt 1):56-9 PMID: 14646134
  8. Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll.
    Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6629-34 PMID: 16618927
  9. Structure of the C-terminal domain of Tup1, a corepressor of transcription in yeast.
    EMBO J. 2000 Jun 15;19(12):3016-27 PMID: 10856245
  10. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex.
    Mol Cell. 2004 Jul 2;15(1):57-67 PMID: 15225548
  11. COMPASS: a complex of proteins associated with a trithorax-related SET domain protein.
    Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):12902-7 PMID: 11687631
  12. Regulation of chromatin structure by site-specific histone H3 methyltransferases.
    Nature. 2000 Aug 10;406(6796):593-9 PMID: 10949293
  13. The language of covalent histone modifications.
    Nature. 2000 Jan 6;403(6765):41-5 PMID: 10638745
  14. MLL targets SET domain methyltransferase activity to Hox gene promoters.
    Mol Cell. 2002 Nov;10(5):1107-17 PMID: 12453418
  15. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF.
    Nature. 2006 Jul 6;442(7098):91-5 PMID: 16728978
  16. Structure and catalytic mechanism of the human histone methyltransferase SET7/9.
    Nature. 2003 Feb 6;421(6923):652-6 PMID: 12540855
  17. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation.
    Mol Cell. 2002 Nov;10(5):1119-28 PMID: 12453419
  18. Linking covalent histone modifications to epigenetics: the rigidity and plasticity of the marks.
    Cold Spring Harb Symp Quant Biol. 2004;69:161-9 PMID: 16117646
  19. Crystallography & NMR system: A new software suite for macromolecular structure determination.
    Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21 PMID: 9757107
  20. A trithorax-group complex purified from Saccharomyces cerevisiae is required for methylation of histone H3.
    Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):90-4 PMID: 11752412
  21. Strength of the Calpha H..O hydrogen bond of amino acid residues.
    J Biol Chem. 2001 Mar 30;276(13):9832-7 PMID: 11152477
  22. Use of TLS parameters to model anisotropic displacements in macromolecular refinement.
    Acta Crystallogr D Biol Crystallogr. 2001 Jan;57(Pt 1):122-33 PMID: 11134934
  23. Refinement of macromolecular structures by the maximum-likelihood method.
    Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55 PMID: 15299926
  24. Structure of crystalline alpha-chymotrypsin. IV. The structure of indoleacryloyl-alpha-chyotrypsin and its relevance to the hydrolytic mechanism of the enzyme.
    J Mol Biol. 1970 Dec 14;54(2):341-54 PMID: 5494034
  25. The Amber biomolecular simulation programs.
    J Comput Chem. 2005 Dec;26(16):1668-88 PMID: 16200636
  26. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins.
    Nature. 2001 Mar 1;410(6824):116-20 PMID: 11242053
  27. Groucho/TLE family proteins and transcriptional repression.
    Gene. 2000 May 16;249(1-2):1-16 PMID: 10831834
  28. Methylation of histone H3 Lys 4 in coding regions of active genes.
    Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8695-700 PMID: 12060701
  29. Role of histone H3 lysine 27 methylation in Polycomb-group silencing.
    Science. 2002 Nov 1;298(5595):1039-43 PMID: 12351676
  30. Regulation of MLL1 H3K4 methyltransferase activity by its core components.
    Nat Struct Mol Biol. 2006 Aug;13(8):713-9 PMID: 16878130
  31. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus.
    Mol Cell. 2004 Feb 27;13(4):587-97 PMID: 14992727
  32. Active genes are tri-methylated at K4 of histone H3.
    Nature. 2002 Sep 26;419(6905):407-11 PMID: 12353038
  33. The CCP4 suite: programs for protein crystallography.
    Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3 PMID: 15299374
  34. Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5.
    Mol Cell. 2006 Apr 7;22(1):137-44 PMID: 16600877
  35. MLL associates specifically with a subset of transcriptionally active target genes.
    Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14765-70 PMID: 16199523
  36. Translating the histone code.
    Science. 2001 Aug 10;293(5532):1074-80 PMID: 11498575
  37. WD dipeptide motifs and LXXLL motif of chicken HIRA are essential for interactions with the p48 subunit of chromatin assembly factor-1 and histone deacetylase-2 in vitro and in vivo.
    Gene. 2004 Nov 10;342(1):125-36 PMID: 15527972
  38. Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A.
    Science. 2006 May 5;312(5774):748-51 PMID: 16601153
  39. Coot: model-building tools for molecular graphics.
    Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32 PMID: 15572765
  40. Altered Hox expression and segmental identity in Mll-mutant mice.
    Nature. 1995 Nov 30;378(6556):505-8 PMID: 7477409
  41. Double chromodomains cooperate to recognize the methylated histone H3 tail.
    Nature. 2005 Dec 22;438(7071):1181-5 PMID: 16372014
  42. Pushing the boundaries of molecular replacement with maximum likelihood.
    Acta Crystallogr D Biol Crystallogr. 2001 Oct;57(Pt 10):1373-82 PMID: 11567148
  43. The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4.
    EMBO J. 2001 Dec 17;20(24):7137-48 PMID: 11742990
  44. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability.
    Cell. 2001 Nov 2;107(3):323-37 PMID: 11701123
  45. Structural basis for the product specificity of histone lysine methyltransferases.
    Mol Cell. 2003 Jul;12(1):177-85 PMID: 12887903
  46. Genomic maps and comparative analysis of histone modifications in human and mouse.
    Cell. 2005 Jan 28;120(2):169-81 PMID: 15680324
  47. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail.
    Science. 2002 Mar 15;295(5562):2080-3 PMID: 11859155
  48. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development.
    Cell. 2005 Jun 17;121(6):859-72 PMID: 15960974
  49. Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae.
    Genes Dev. 2001 Dec 15;15(24):3286-95 PMID: 11751634
  50. Catalytic properties and kinetic mechanism of human recombinant Lys-9 histone H3 methyltransferase SUV39H1: participation of the chromodomain in enzymatic catalysis.
    Biochemistry. 2006 Mar 14;45(10):3272-84 PMID: 16519522
Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9993
DOI
10.1038/nsmb1119
Published
2006-08-00
Epub
2006-00-09
Pages
704-12
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC4698793
Subset
IM
Grants
NCI NIH HHS · P30 CA008748 · United States
NIGMS NIH HHS · R01 GM044853 · United States
Databases
PDB
2CNX, 2CO0, 2H68, 2H6K, 2H6N, 2H6Q
External Links
PubMed source DOI: 10.1038/nsmb1119 PMC Full Text View journal details
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