5t0k

From Proteopedia

Jump to: navigation, search

Structure of G9a SET-domain with H3K9M mutant peptide and SAM

Structural highlights

5t0k is a 4 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 1.7Å
Ligands:SAM, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

EHMT2_HUMAN Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also mediates monomethylation of 'Lys-56' of histone H3 (H3K56me1) in G1 phase, leading to promote interaction between histone H3 and PCNA and regulating DNA replication. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. May also methylate histone H1. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. Also methylates CDYL, WIZ, ACIN1, DNMT1, HDAC1, ERCC6, KLF12 and itself.[1] [2] [3] [4] [5]

Publication Abstract from PubMed

Histone lysine-to-methionine (K-to-M) mutations are associated with multiple cancers, and they function in a dominant fashion to block the methylation of corresponding lysines on wild type histones. However, their mechanisms of function are controversial. Here we show that in fission yeast, introducing the K9M mutation into one of the three histone H3 genes dominantly blocks H3K9 methylation on wild type H3 across the genome. In addition, H3K9M enhances the interaction of histone H3 tail with the H3K9 methyltransferase Clr4 in a SAM (S-adenosyl-methionine)-dependent manner, and Clr4 is trapped at nucleation sites to prevent its spreading and the formation of large heterochromatin domains. We further determined the crystal structure of an H3K9M peptide in complex with human H3K9 methyltransferase G9a and SAM, which reveales that the methionine side chain had enhanced van der Waals interactions with G9a. Therefore, our results provide a detailed mechanism by which H3K9M regulates H3K9 methylation.

A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading.,Shan CM, Wang J, Xu K, Chen H, Yue JX, Andrews S, Moresco JJ, Yates JR, Nagy PL, Tong L, Jia S Elife. 2016 Sep 20;5. pii: e17903. doi: 10.7554/eLife.17903. PMID:27648579[6]

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

Loading citation details..
Citations
reviews cite this structure
-1 more
other articles
No citations found

See Also

References

  1. ↑ Milner CM, Campbell RD. The G9a gene in the human major histocompatibility complex encodes a novel protein containing ankyrin-like repeats. Biochem J. 1993 Mar 15;290 ( Pt 3):811-8. PMID:8457211
  2. ↑ Tachibana M, Sugimoto K, Fukushima T, Shinkai Y. Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J Biol Chem. 2001 Jul 6;276(27):25309-17. Epub 2001 Apr 20. PMID:11316813 doi:10.1074/jbc.M101914200
  3. ↑ Rathert P, Dhayalan A, Murakami M, Zhang X, Tamas R, Jurkowska R, Komatsu Y, Shinkai Y, Cheng X, Jeltsch A. Protein lysine methyltransferase G9a acts on non-histone targets. Nat Chem Biol. 2008 Jun;4(6):344-6. doi: 10.1038/nchembio.88. Epub 2008 Apr 27. PMID:18438403 doi:10.1038/nchembio.88
  4. ↑ Huang J, Dorsey J, Chuikov S, Zhang X, Jenuwein T, Reinberg D, Berger SL. G9A and GLP methylate lysine 373 in the tumor suppressor p53. J Biol Chem. 2010 Jan 29. PMID:20118233 doi:M109.062588
  5. ↑ Yu Y, Song C, Zhang Q, DiMaggio PA, Garcia BA, York A, Carey MF, Grunstein M. Histone H3 lysine 56 methylation regulates DNA replication through its interaction with PCNA. Mol Cell. 2012 Apr 13;46(1):7-17. doi: 10.1016/j.molcel.2012.01.019. Epub 2012, Mar 1. PMID:22387026 doi:10.1016/j.molcel.2012.01.019
  6. ↑ Shan CM, Wang J, Xu K, Chen H, Yue JX, Andrews S, Moresco JJ, Yates JR, Nagy PL, Tong L, Jia S. A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading. Elife. 2016 Sep 20;5. pii: e17903. doi: 10.7554/eLife.17903. PMID:27648579 doi:http://dx.doi.org/10.7554/eLife.17903

Contents


PDB ID 5t0k

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/5t0k"
Personal tools