3f9y

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Structural Insights into Lysine Multiple Methylation by SET Domain Methyltransferases, SET8-Y334F / H4-Lys20me1 / AdoHcy

Structural highlights

3f9y 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 1.5Å
Ligands:MLZ, SAH
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KMT5A_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. Plays a negative role in TGF-beta response regulation and a positive role in cell migration.[1] [2] [3] [4] [5] [6] [7] [8]

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

SET domain protein lysine methyltransferases (PKMTs) regulate transcription and other cellular functions through site-specific methylation of histones and other substrates. PKMTs catalyze the formation of monomethylated, dimethylated, or trimethylated products, establishing an additional hierarchy with respect to methyllysine recognition in signaling. Biochemical studies of PKMTs have identified a conserved position within their active sites, the Phe/Tyr switch, that governs their respective product specificities. To elucidate the mechanism underlying this switch, we have characterized a Phe/Tyr switch mutant of the histone H4 Lys-20 (H4K20) methyltransferase SET8, which alters its specificity from a monomethyltransferase to a dimethyltransferase. The crystal structures of the SET8 Y334F mutant bound to histone H4 peptides bearing unmodified, monomethyl, and dimethyl Lys-20 reveal that the phenylalanine substitution attenuates hydrogen bonding to a structurally conserved water molecule adjacent to the Phe/Tyr switch, facilitating its dissociation. The additional space generated by the solvent's dissociation enables the monomethyllysyl side chain to adopt a conformation that is catalytically competent for dimethylation and furnishes sufficient volume to accommodate the dimethyl epsilon-ammonium product. Collectively, these results indicate that the Phe/Tyr switch regulates product specificity through altering the affinity of an active-site water molecule whose dissociation is required for lysine multiple methylation.

Structural origins for the product specificity of SET domain protein methyltransferases.,Couture JF, Dirk LM, Brunzelle JS, Houtz RL, Trievel RC Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20659-64. Epub 2008 Dec 16. PMID:19088188[9]

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

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Citations
13 reviews cite this structure
Carbon-oxygen hydrogen bonding in biological structure and function.
Horowitz et al. (2012)
12 more
55 other articles
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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ Abbas T, Mueller AC, Shibata E, Keaton M, Rossi M, Dutta A. CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration. Mol Cell. 2013 Mar 28;49(6):1147-58. doi: 10.1016/j.molcel.2013.02.003. Epub 2013, Mar 7. PMID:23478445 doi:http://dx.doi.org/10.1016/j.molcel.2013.02.003
  9. ↑ Couture JF, Dirk LM, Brunzelle JS, Houtz RL, Trievel RC. Structural origins for the product specificity of SET domain protein methyltransferases. Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20659-64. Epub 2008 Dec 16. PMID:19088188

Contents


PDB ID 3f9y

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