4bup

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A novel route to product specificity in the Suv4-20 family of histone H4K20 methyltransferases

Structural highlights

4bup is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.166Å
Ligands:GOL, SAM, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KMT5B_MOUSE Histone methyltransferase that specifically methylates monomethylated 'Lys-20' (H4K20me1) and dimethylated 'Lys-20' (H4K20me2) of histone H4 to produce respectively dimethylated 'Lys-20' (H4K20me2) and trimethylated 'Lys-20' (H4K20me3) and thus regulates transcription and maintenance of genome integrity (PubMed:28114273, PubMed:24049080, PubMed:15145825). In vitro also methylates unmodified 'Lys-20' (H4K20me0) of histone H4 and nucleosomes (By similarity). H4 'Lys-20' trimethylation represents a specific tag for epigenetic transcriptional repression (PubMed:15145825). Mainly functions in pericentric heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin in these regions (PubMed:15145825). KMT5B is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2) (PubMed:16612004, PubMed:15750587). Plays a role in myogenesis by regulating the expression of target genes, such as EID3 (PubMed:23720823). Facilitates TP53BP1 foci formation upon DNA damage and proficient non-homologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation of 'Lys-20' of histone H4 (By similarity). May play a role in class switch reconbination by catalyzing the di- and trimethylation of 'Lys-20' of histone H4 (PubMed:28114273).[UniProtKB:Q4FZB7][1] [2] [3] [4] [5] [6]

Publication Abstract from PubMed

The delivery of site-specific post-translational modifications to histones generates an epigenetic regulatory network that directs fundamental DNA-mediated processes and governs key stages in development. Methylation of histone H4 lysine-20 has been implicated in DNA repair, transcriptional silencing, genomic stability and regulation of replication. We present the structure of the histone H4K20 methyltransferase Suv4-20h2 in complex with its histone H4 peptide substrate and S-adenosyl methionine cofactor. Analysis of the structure reveals that the Suv4-20h2 active site diverges from the canonical SET domain configuration and generates a high degree of both substrate and product specificity. Together with supporting biochemical data comparing Suv4-20h1 and Suv4-20h2, we demonstrate that the Suv4-20 family enzymes take a previously mono-methylated H4K20 substrate and generate an exclusively di-methylated product. We therefore predict that other enzymes are responsible for the tri-methylation of histone H4K20 that marks silenced heterochromatin.

A novel route to product specificity in the Suv4-20 family of histone H4K20 methyltransferases.,Southall SM, Cronin NB, Wilson JR Nucleic Acids Res. 2013 Sep 18. PMID:24049080[7]

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

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Citations
8 reviews cite this structure
Writing, erasing and reading histone lysine methylations.
Hyun et al. (2017)
7 more
9 other articles
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See Also

References

  1. ↑ Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G, Reinberg D, Jenuwein T. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 2004 Jun 1;18(11):1251-62. Epub 2004 May 14. PMID:15145825 doi:http://dx.doi.org/10.1101/gad.300704
  2. ↑ Gonzalo S, Garcia-Cao M, Fraga MF, Schotta G, Peters AH, Cotter SE, Eguia R, Dean DC, Esteller M, Jenuwein T, Blasco MA. Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol. 2005 Apr;7(4):420-8. doi: 10.1038/ncb1235. Epub 2005 Mar 6. PMID:15750587 doi:http://dx.doi.org/10.1038/ncb1235
  3. ↑ Isaac CE, Francis SM, Martens AL, Julian LM, Seifried LA, Erdmann N, Binne UK, Harrington L, Sicinski P, Berube NG, Dyson NJ, Dick FA. The retinoblastoma protein regulates pericentric heterochromatin. Mol Cell Biol. 2006 May;26(9):3659-71. PMID:16612004 doi:http://dx.doi.org/26/9/3659
  4. ↑ Neguembor MV, Xynos A, Onorati MC, Caccia R, Bortolanza S, Godio C, Pistoni M, Corona DF, Schotta G, Gabellini D. FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis. J Mol Cell Biol. 2013 Oct;5(5):294-307. doi: 10.1093/jmcb/mjt018. Epub 2013 May, 29. PMID:23720823 doi:http://dx.doi.org/10.1093/jmcb/mjt018
  5. ↑ Southall SM, Cronin NB, Wilson JR. A novel route to product specificity in the Suv4-20 family of histone H4K20 methyltransferases. Nucleic Acids Res. 2013 Sep 18. PMID:24049080 doi:10.1093/nar/gkt776
  6. ↑ Bromberg KD, Mitchell TR, Upadhyay AK, Jakob CG, Jhala MA, Comess KM, Lasko LM, Li C, Tuzon CT, Dai Y, Li F, Eram MS, Nuber A, Soni NB, Manaves V, Algire MA, Sweis RF, Torrent M, Schotta G, Sun C, Michaelides MR, Shoemaker AR, Arrowsmith CH, Brown PJ, Santhakumar V, Martin A, Rice JC, Chiang GG, Vedadi M, Barsyte-Lovejoy D, Pappano WN. The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity. Nat Chem Biol. 2017 Mar;13(3):317-324. doi: 10.1038/nchembio.2282. Epub 2017 Jan , 23. PMID:28114273 doi:http://dx.doi.org/10.1038/nchembio.2282
  7. ↑ Southall SM, Cronin NB, Wilson JR. A novel route to product specificity in the Suv4-20 family of histone H4K20 methyltransferases. Nucleic Acids Res. 2013 Sep 18. PMID:24049080 doi:10.1093/nar/gkt776

Contents


PDB ID 4bup

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