|PDB||RCSB PDB PDBj PDBe PDBsum|
|基因本体||AmiGO / EGO|
These small changes alter the target residue site specificity for methylation and allow the SET domain methyltransferases to target many different residues. This interplay between the pre-SET domain and the catalytic core is critical for enzyme function.
In order for the reaction to proceed, S-Adenosyl methionine (SAM) and the lysine residue of the substrate histone tail must first be bound and properly oriented in the catalytic pocket of the SET domain. Next, a nearby tyrosine residue deprotonates the ε-amino group of the lysine residue. The lysine chain then makes a nucleophilic attack on the methyl group on the sulfur atom of the SAM molecule, transferring the methyl group to the lysine side chain.
Instead of SET, non-SET domain-containing histone methyltransferase utilizes the enzyme Dot1. Unlike the SET domain, which targets the lysine tail region of the histone, Dot1 methylates a lysine residue in the globular core of the histone, and is the only enzyme known to do so. A possible homolog of Dot1 was found in archaea which shows the ability to methylate archaeal histone-like protein in recent studies.
The N terminal of Dot1 contains the active site. A loop serving as the binding site for SAM links the N-terminal and the C-terminal domains of the Dot1 catalytic domain. The C-terminal is important for the substrate specificity and binding of Dot1 because the region carries a positive charge, allowing for a favorable interaction with the negatively charged backbone of DNA. Due to structural constraints, Dot1 is only able to methylate histone H3.
There are two different types of protein arginine methyltransferases (PRMTs) and three types of methylation that can occur at arginine residues on histone tails. The first type of PRMTs (PRMT1, PRMT3, CARM1⧸PRMT4, and Rmt1⧸Hmt1) produce monomethylarginine and asymmetric dimethylarginine. The second type (JBP1⧸PRMT5) produces monomethyl or symmetric dimethylarginine. The differences in the two types of PRMTs arise from restrictions in the arginine binding pocket.
The catalytic domain of PRMTs consists of a SAM binding domain and substrate binding domain (about 310 amino acids in total). Each PRMT has a unique N-terminal region and a catalytic core. The arginine residue and SAM must be correctly oriented within the binding pocket. SAM is secured inside the pocket by a hydrophobic interaction between an adenine ring and a phenyl ring of a phenylalanine.
A glutamate on a nearby loop interacts with nitrogens on the target arginine residue. This interaction redistributes the positive charge and leads to the deprotonation of one nitrogen group, which can then make a nucleophilic attack on the methyl group of SAM. Differences between the two types of PRMTs determine the next methylation step: either catalyzing the dimethylation of one nitrogen or allowing the symmetric methylation of both groups. However, in both cases the proton stripped from the nitrogen is dispersed through a histidine–aspartate proton relay system and released into the surrounding matrix.
Histone methylation plays an important role in epigenetic gene regulation. Methylated histones can either repress or activate transcription as different experimental findings suggest. For example, it is likely that the methylation of lysine 9 on histone H3 (H3K9me3) in the promoter region of genes prevents excessive expression of these genes and, therefore, delays cell cycle transition and/or proliferation. See Histone#Chromatin regulation.
Abnormal expression or activity of methylation-regulating enzymes has been noted in some types of human cancers, suggesting associations between histone methylation and malignant transformation of cells or formation of tumors. In recent years, epigenetic modification of the histone proteins, especially the methylation of the histone H3, in cancer development has been an area of emerging research. It is now generally accepted that in addition to genetic aberrations, cancer can be initiated by epigenetic changes in which gene expression is altered without genomic abnormalities. These epigenetic changes include loss or gain of methylations in both DNA and histone proteins.
There is not yet compelling evidence that suggests cancers develop purely by abnormalities in histone methylation or its signaling pathways, however they may be a contributing factor. For example, down-regulation of methylation of lysine 9 on histone 3 (H3K9me3) has been observed in several types of human cancer (such as colorectal cancer, ovarian cancer, and lung cancer), which arise from either the deficiency of H3K9 methyltransferases or elevated activity or expression of H3K9 demethylases.
- Wood A. Posttranslational Modifications of Histones by Methylation. (编) Conaway JW, Conaway RC. Proteins in eukaryotic transcription. Advances in Protein Chemistry 67. Amsterdam: Elsevier Academic Press. 2004: 201–222. ISBN 0-12-034267-7. doi:10.1016/S0065-3233(04)67008-2.
- Trievel RC, Beach BM, Dirk LM, Houtz RL, Hurley JH. Structure and catalytic mechanism of a SET domain protein methyltransferase. Cell. October 2002, 111 (1): 91–103. PMID 12372303. doi:10.1016/S0092-8674(02)01000-0.
- Min J, Feng Q, Li Z, Zhang Y, Xu RM. Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell. March 2003, 112 (5): 711–23. PMID 12628190. doi:10.1016/S0092-8674(03)00114-4.
- Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, Aswad DW, Stallcup MR. Regulation of transcription by a protein methyltransferase. Science. June 1999, 284 (5423): 2174–7. PMID 10381882. doi:10.1126/science.284.5423.2174.
- Gary JD, Lin WJ, Yang MC, Herschman HR, Clarke S. The predominant protein-arginine methyltransferase from Saccharomyces cerevisiae. J. Biol. Chem. May 1996, 271 (21): 12585–94. PMID 8647869. doi:10.1074/jbc.271.21.12585.
- McBride AE, Weiss VH, Kim HK, Hogle JM, Silver PA. Analysis of the yeast arginine methyltransferase Hmt1p/Rmt1p and its in vivo function. Cofactor binding and substrate interactions. J. Biol. Chem. February 2000, 275 (5): 3128–36. PMID 10652296. doi:10.1074/jbc.275.5.3128.
- McBride AE, Silver PA. State of the arg: protein methylation at arginine comes of age. Cell. July 2001, 106 (1): 5–8. PMID 11461695. doi:10.1016/S0092-8674(01)00423-8.
- Fersht AR, Sperling J. The charge relay system in chymotrypsin and chymotrypsinogen. J. Mol. Biol. February 1973, 74 (2): 137–49. PMID 4689953. doi:10.1016/0022-2836(73)90103-4.
- Chen F, Kan H, Castranova V. Methylation of Lysine 9 of Histone H3: Role of Heterochromatin Modulation and Tumorigenesis. (编) Tollefsbol TO. Handbook of Epigenetics: The New Molecular and Medical Genetics. Boston: Academic Press. 2010: 149–157. ISBN 0-12-375709-6. doi:10.1016/B978-0-12-375709-8.00010-1.
- Espino PS, Drobic B, Dunn KL, Davie JR. Histone modifications as a platform for cancer therapy. J. Cell. Biochem. April 2005, 94 (6): 1088–102. PMID 15723344. doi:10.1002/jcb.20387.
- Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, Yagyu R, Nakamura Y. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat. Cell Biol. August 2004, 6 (8): 731–40. PMID 15235609. doi:10.1038/ncb1151.
- Trievel RC. Structure and function of histone methyltransferases. Crit. Rev. Eukaryot. Gene Expr. 2004, 14 (3): 147–69. PMID 15248813. doi:10.1615/CritRevEukaryotGeneExpr.v14.i3.10.
- Conde F, Refolio E, Cordón-Preciado V, Cortés-Ledesma F, Aragón L, Aguilera A, San-Segundo PA. The Dot1 histone methyltransferase and the Rad9 checkpoint adaptor contribute to cohesin-dependent double-strand break repair by sister chromatid recombination in Saccharomyces cerevisiae. Genetics. June 2009, 182 (2): 437–46. PMC 2691753. PMID 19332880. doi:10.1534/genetics.109.101899.
- GeneReviews/NCBI/NIH/UW entry on Kleefstra Syndrome