Proteopedia

5hq2

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Structural model of Set8 histone H4 Lys20 methyltransferase bound to nucleosome core particleStructural model of Set8 histone H4 Lys20 methyltransferase bound to nucleosome core particle

Structural highlights

5hq2 is a 8 chain structure with sequence from [1], African clawed frog, Baker's yeast and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:hist1h2aj, LOC494591 (African clawed frog), SRM1, MTR1, PRP20, YGL097W (Baker's yeast), SETD8, KMT5A, PRSET7, SET07, SET8 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[RCC1_YEAST] Guanine nucleotide exchange factor that promotes the exchange of GSP1/GSP2-bound GDP by GTP and controls RNA metabolism and transport. Involved in yeast pheromone response pathway and in mRNA metabolism. Involved in nuclear pore complex (NPC) assembly and required for mRNA and ribosome nuclear export. Binds chromatin and is involved NPC-mediated transcriptional control.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [H4_XENLA] Core component of nucleosome. 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. [SETD8_HUMAN] Protein-lysine N-methyltransferase that monomethylates both histones and non-histone proteins. Specifically monomethylates 'Lys-20' of histone H4 (H4K20me1). H4K20me1 is enriched during mitosis and represents a specific tag for epigenetic transcriptional repression. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. Required for cell proliferation, probably by contributing to the maintenance of proper higher-order structure of DNA during mitosis. Involved in chromosome condensation and proper cytokinesis. Nucleosomes are preferred as substrate compared to free histones. Mediates monomethylation of p53/TP53 at 'Lys-382', leading to repress p53/TP53-target genes.[15] [16] [17] [18] [19] [20] [21] [H32_XENLA] Core component of nucleosome. 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. [H2B11_XENLA] Core component of nucleosome. 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.

Publication Abstract from PubMed

Set8 is the only mammalian monomethyltransferase responsible for H4K20me1, a methyl mark critical for genomic integrity of eukaryotic cells. We present here a structural model for how Set8 uses multivalent interactions to bind and methylate the nucleosome based on crystallographic and solution studies of the Set8/nucleosome complex. Our studies indicate that Set8 employs its i-SET and c-SET domains to engage nucleosomal DNA 1 to 1.5 turns from the nucleosomal dyad and in doing so, it positions the SET domain for catalysis with H4 Lys20. Surprisingly, we find that a basic N-terminal extension to the SET domain plays an even more prominent role in nucleosome binding, possibly by making an arginine anchor interaction with the nucleosome H2A/H2B acidic patch. We further show that proliferating cell nuclear antigen and the nucleosome compete for binding to Set8 through this basic extension, suggesting a mechanism for how nucleosome binding protects Set8 from proliferating cell nuclear antigen-dependent degradation during the cell cycle.

Multivalent Interactions by the Set8 Histone Methyltransferase With Its Nucleosome Substrate.,Girish TS, McGinty RK, Tan S J Mol Biol. 2016 Apr 24;428(8):1531-43. doi: 10.1016/j.jmb.2016.02.025. Epub 2016, Mar 4. PMID:26953260[22]

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

See Also

References

  1. ↑ Clark KL, Sprague GF Jr. Yeast pheromone response pathway: characterization of a suppressor that restores mating to receptorless mutants. Mol Cell Biol. 1989 Jun;9(6):2682-94. PMID:2548085
  2. ↑ Aebi M, Clark MW, Vijayraghavan U, Abelson J. A yeast mutant, PRP20, altered in mRNA metabolism and maintenance of the nuclear structure, is defective in a gene homologous to the human gene RCC1 which is involved in the control of chromosome condensation. Mol Gen Genet. 1990 Oct;224(1):72-80. PMID:2277633
  3. ↑ Clark KL, Ohtsubo M, Nishimoto T, Goebl M, Sprague GF Jr. The yeast SRM1 protein and human RCC1 protein share analogous functions. Cell Regul. 1991 Oct;2(10):781-92. PMID:1666302
  4. ↑ Fleischmann M, Clark MW, Forrester W, Wickens M, Nishimoto T, Aebi M. Analysis of yeast prp20 mutations and functional complementation by the human homologue RCC1, a protein involved in the control of chromosome condensation. Mol Gen Genet. 1991 Jul;227(3):417-23. PMID:1865879
  5. ↑ Forrester W, Stutz F, Rosbash M, Wickens M. Defects in mRNA 3'-end formation, transcription initiation, and mRNA transport associated with the yeast mutation prp20: possible coupling of mRNA processing and chromatin structure. Genes Dev. 1992 Oct;6(10):1914-26. PMID:1398069
  6. ↑ Amberg DC, Fleischmann M, Stagljar I, Cole CN, Aebi M. Nuclear PRP20 protein is required for mRNA export. EMBO J. 1993 Jan;12(1):233-41. PMID:7679070
  7. ↑ Kirkpatrick D, Solomon F. Overexpression of yeast homologs of the mammalian checkpoint gene RCC1 suppresses the class of alpha-tubulin mutations that arrest with excess microtubules. Genetics. 1994 Jun;137(2):381-92. PMID:8070652
  8. ↑ Hurt E, Hannus S, Schmelzl B, Lau D, Tollervey D, Simos G. A novel in vivo assay reveals inhibition of ribosomal nuclear export in ran-cycle and nucleoporin mutants. J Cell Biol. 1999 Feb 8;144(3):389-401. PMID:9971735
  9. ↑ Stage-Zimmermann T, Schmidt U, Silver PA. Factors affecting nuclear export of the 60S ribosomal subunit in vivo. Mol Biol Cell. 2000 Nov;11(11):3777-89. PMID:11071906
  10. ↑ Brodsky AS, Silver PA. Pre-mRNA processing factors are required for nuclear export. RNA. 2000 Dec;6(12):1737-49. PMID:11142374
  11. ↑ Baker RP, Harreman MT, Eccleston JF, Corbett AH, Stewart M. Interaction between Ran and Mog1 is required for efficient nuclear protein import. J Biol Chem. 2001 Nov 2;276(44):41255-62. Epub 2001 Aug 16. PMID:11509570 doi:10.1074/jbc.M106060200
  12. ↑ Clement M, Lavallee F, Barbes-Morin G, de Repentigny L, Belhumeur P. Overexpression of Bud5p can suppress mutations in the Gsp1p guanine nucleotide exchange factor Prp20p in Saccharomyces cerevisiae. Mol Genet Genomics. 2001 Sep;266(1):20-7. PMID:11589573
  13. ↑ Ryan KJ, McCaffery JM, Wente SR. The Ran GTPase cycle is required for yeast nuclear pore complex assembly. J Cell Biol. 2003 Mar 31;160(7):1041-53. Epub 2003 Mar 24. PMID:12654904 doi:10.1083/jcb.200209116
  14. ↑ Dilworth DJ, Tackett AJ, Rogers RS, Yi EC, Christmas RH, Smith JJ, Siegel AF, Chait BT, Wozniak RW, Aitchison JD. The mobile nucleoporin Nup2p and chromatin-bound Prp20p function in endogenous NPC-mediated transcriptional control. J Cell Biol. 2005 Dec 19;171(6):955-65. PMID:16365162 doi:10.1083/jcb.200509061
  15. ↑ Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang Y, Chuikov S, Valenzuela P, Tempst P, Steward R, Lis JT, Allis CD, Reinberg D. PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol Cell. 2002 Jun;9(6):1201-13. PMID:12086618
  16. ↑ Fang J, Feng Q, Ketel CS, Wang H, Cao R, Xia L, Erdjument-Bromage H, Tempst P, Simon JA, Zhang Y. Purification and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase. Curr Biol. 2002 Jul 9;12(13):1086-99. PMID:12121615
  17. ↑ Julien E, Herr W. A switch in mitotic histone H4 lysine 20 methylation status is linked to M phase defects upon loss of HCF-1. Mol Cell. 2004 Jun 18;14(6):713-25. PMID:15200950 doi:http://dx.doi.org/10.1016/j.molcel.2004.06.008
  18. ↑ Sims JK, Houston SI, Magazinnik T, Rice JC. A trans-tail histone code defined by monomethylated H4 Lys-20 and H3 Lys-9 demarcates distinct regions of silent chromatin. J Biol Chem. 2006 May 5;281(18):12760-6. Epub 2006 Mar 3. PMID:16517599 doi:http://dx.doi.org/10.1074/jbc.M513462200
  19. ↑ Shi X, Kachirskaia I, Yamaguchi H, West LE, Wen H, Wang EW, Dutta S, Appella E, Gozani O. Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol Cell. 2007 Aug 17;27(4):636-46. PMID:17707234 doi:http://dx.doi.org/10.1016/j.molcel.2007.07.012
  20. ↑ Xiao B, Jing C, Kelly G, Walker PA, Muskett FW, Frenkiel TA, Martin SR, Sarma K, Reinberg D, Gamblin SJ, Wilson JR. Specificity and mechanism of the histone methyltransferase Pr-Set7. Genes Dev. 2005 Jun 15;19(12):1444-54. Epub 2005 Jun 2. PMID:15933069 doi:http://dx.doi.org/10.1101/gad.1315905
  21. ↑ Couture JF, Collazo E, Brunzelle JS, Trievel RC. Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Genes Dev. 2005 Jun 15;19(12):1455-65. Epub 2005 Jun 2. PMID:15933070 doi:10.1101/gad.1318405
  22. ↑ Girish TS, McGinty RK, Tan S. Multivalent Interactions by the Set8 Histone Methyltransferase With Its Nucleosome Substrate. J Mol Biol. 2016 Apr 24;428(8):1531-43. doi: 10.1016/j.jmb.2016.02.025. Epub 2016, Mar 4. PMID:26953260 doi:http://dx.doi.org/10.1016/j.jmb.2016.02.025

5hq2, resolution 4.50Å

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