Summary: HsdM N-terminal domain
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DNA methyltransferase Edit Wikipedia article
|N-6 DNA Methylase|
crystal structure of type i restriction enzyme ecoki m protein (ec 126.96.36.199) (m.ecoki)
|HsdM N-terminal domain|
|C-5 cytosine-specific DNA methylase|
structure of human dnmt2, an enigmatic dna methyltransferase homologue
crystal structure of methyltransferase mboiia (moraxella bovis)
In biochemistry, the DNA methyltransferase (DNA MTase) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.
MTases can be divided into three different groups on the basis of the chemical reactions they catalyze:
- m6A - those that generate N6-methyladenine EC 188.8.131.52
- m4C - those that generate N4-methylcytosine EC 184.108.40.206
- m5C - those that generate C5-methylcytosine EC 220.127.116.11
m6A and m4C methyltransferases are found primarily in prokaryotes. m5C methyltransfereases are found in some lower eukaryotes, in most higher plants, and in animals beginning with the echinoderms.
m6A methyltransferases (N-6 adenine-specific DNA methylase) (A-Mtase) are enzymes that specifically methylate the amino group at the C-6 position of adenines in DNA. They are found in the three existing types of bacterial restriction-modification systems (in type I system the A-Mtase is the product of the hsdM gene, and in type III it is the product of the mod gene). These enzymes are responsible for the methylation of specific DNA sequences in order to prevent the host from digesting its own genome via its restriction enzymes. These methylases have the same sequence specificity as their corresponding restriction enzymes. These enzymes contain a conserved motif Asp/Asn-Pro-Pro-Tyr/Phe in their N-terminal section, this conserved region could be involved in substrate binding or in the catalytic activity. The structure of N6-MTase TaqI (M.TaqI) has been resolved to 2.4 A. The molecule folds into 2 domains, an N-terminal catalytic domain, which contains the catalytic and cofactor binding sites, and comprises a central 9-stranded beta-sheet, surrounded by 5 helices; and a C-terminal DNA recognition domain, which is formed by 4 small beta-sheets and 8 alpha-helices. The N- and C-terminal domains form a cleft that accommodates the DNA substrate. A classification of N-MTases has been proposed, based on conserved motif (CM) arrangements. According to this classification, N6-MTases that have a DPPY motif (CM II) occurring after the FxGxG motif (CM I) are designated D12 class N6-adenine MTases. The type I restriction and modification system is composed of three polypeptides R, M and S. The M (hsdM) and S subunits together form a methyltransferase that methylates two adenine residues in complementary strands of a bipartite DNA recognition sequence. In the presence of the R subunit, the complex can also act as an endonuclease, binding to the same target sequence but cutting the DNA some distance from this site. Whether the DNA is cut or modified depends on the methylation state of the target sequence. When the target site is unmodified, the DNA is cut. When the target site is hemimethylated, the complex acts as a maintenance methyltransferase, modifying the DNA so that both strands become methylated. hsdM contains an alpha-helical domain at the N-terminus, the HsdM N-terminal domain.
m4C methyltransferases (N-4 cytosine-specific DNA methylases) are enzymes that specifically methylate the amino group at the C-4 position of cytosines in DNA. Such enzymes are found as components of type II restriction-modification systems in prokaryotes. Such enzymes recognise a specific sequence in DNA and methylate a cytosine in that sequence. By this action they protect DNA from cleavage by type II restriction enzymes that recognise the same sequence
m5C methyltransferases (C-5 cytosine-specific DNA methylase) (C5 Mtase) are enzymes that specifically methylate the C-5 carbon of cytosines in DNA to produce C5-methylcytosine. In mammalian cells, cytosine-specific methyltransferases methylate certain CpG sequences, which are believed to modulate gene expression and cell differentiation. In bacteria, these enzymes are a component of restriction-modification systems and serve as valuable tools for the manipulation of DNA. The structure of HhaI methyltransferase (M.HhaI) has been resolved to 2.5 A: the molecule folds into 2 domains - a larger catalytic domain containing catalytic and cofactor binding sites, and a smaller DNA recognition domain.
De novo vs. maintenance
De novo methyltransferases recognize something in the DNA that allows them to newly methylate cytosines. These are expressed mainly in early embryo development and they set up the pattern of methylation.
Maintenance methyltransferases add methylation to DNA when one strand is already methylated. These work throughout the life of the organism to maintain the methylation pattern that had been established by the de novo methyltransferases IS.
Three active DNA methyltransferases have been identified in mammals. They are named DNMT1, DNMT3A, and DNMT3B. A fourth enzyme previously known as DNMT2 is not a DNA methyltransferase (see below).
DNMT1 is the most abundant DNA methyltransferase in mammalian cells, and considered to be the key maintenance methyltransferase in mammals. It predominantly methylates hemimethylated CpG di-nucleotides in the mammalian genome. This enzyme is 7– to 100-fold more active on hemimethylated DNA as compared with unmethylated substrate in vitro, but it is still more active at de novo methylation than other DNMTs. The recognition motif for the human enzyme involves only three of the bases in the CpG dinuclotide pair: a C on one strand and CpG on the other. This relaxed substrate specificity requirement allows it to methylate unusual structures like DNA slippage intermediates at de novo rates that equal its maintenance rate. Like other DNA cytosine-5 methyltransferases the human enzyme recognizes flipped out cytosines in double stranded DNA and operates by the nucleophilic attack mechanism. In human cancer cells DNMT1 is responsible for both de novo and maintenance methylation of tumor suppressor genes. The enzyme is about 1,620 amino acids long. The first 1,100 amino acids constitute the regulatory domain of the enzyme, and the remaining residues constitute the catalytic domain. These are joined by Gly-Lys repeats. Both domains are required for the catalytic function of DNMT1.
DNMT1 has several isoforms, the somatic DNMT1, a splice variant (DNMT1b) and an oocyte-specific isoform (DNMT1o). DNMT1o is synthesized and stored in the cytoplasm of the oocyte and translocated to the cell nucleus during early embryonic development, while the somatic DNMT1 is always found in the nucleus of somatic tissue.
DNMT1 null mutant embryonic stem cells were viable and contained a small percentage of methylated DNA and methyltransferase activity. Mouse embryos homozygous for a deletion in Dnmt1 die at 10–11 days gestation.
Although this enzyme has strong sequence similarities with 5-methylcytosine methyltransferases of both prokaryotes and eukaryotes, in 2006, the enzyme was shown to methylate position 38 in aspartic acid transfer RNA and does not methylate DNA. To reflect this different function, the name for this methyltransferase has been changed to TRDMT1 (tRNA aspartic acid methyltransferase 1) to better reflect its biological function. TRDMT1 is the first RNA cytosine methyltransferase to be identified in a human.
|This section does not cite any references (sources). (November 2010)|
DNMT3 is a family of DNA methyltransferases that could methylate hemimethylated and unmethylated CpG at the same rate. The architecture of DNMT3 enzymes is similar to that of DNMT1, with a regulatory region attached to a catalytic domain. There are three known members of the DNMT3 family: DNMT3a, 3b, and 3L.
DNMT3a and DNMT3b can mediate methylation-independent gene repression. DNMT3a can co-localize with heterochromatin protein (HP1) and methyl-CpG-binding protein (MeCBP). They can also interact with DNMT1, which might be a co-operative event during DNA methylation. DNMT3a prefers CpG methylation to CpA, CpT, and CpC methylation, though there appears to be some sequence preference of methylation for DNMT3a and DNMT3b. DNMT3a methylates CpG sites at a rate much slower than DNMT1, but greater than DNMT3b.
DNMT3L contains DNA methyltransferase motifs and is required for establishing maternal genomic imprints, despite being catalytically inactive. DNMT3L is expressed during gametogenesis when genomic imprinting takes place. The loss of DNMT3L leads to bi-allelic expression of genes normally not expressed by the maternal allele. DNMT3L interacts with DNMT3a and DNMT3b and co-localized in the nucleus. Though DNMT3L appears incapable of methylation, it may participate in transcriptional repression.
- Vidaza (azacitidine) in phase III trials for Myelodysplastic Syndromes and AML
- Dacogen (decitabine) in phase III trials for AML and CML
- Loenen WA, Daniel AS, Braymer HD, Murray NE (November 1987). "Organization and sequence of the hsd genes of Escherichia coli K-12". J. Mol. Biol. 198 (2): 159–70. doi:10.1016/0022-2836(87)90303-2. PMID 3323532.
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- Labahn J, Granzin J, Schluckebier G, Robinson DP, Jack WE, Schildkraut I, Saenger W (November 1994). "Three-dimensional structure of the adenine-specific DNA methyltransferase M.Taq I in complex with the cofactor S-adenosylmethionine". Proc. Natl. Acad. Sci. U.S.A. 91 (23): 10957–61. doi:10.1073/pnas.91.23.10957. PMC 45145. PMID 7971991.
- Kelleher JE, Daniel AS, Murray NE (1991). "Mutations that confer de novo activity upon a maintenance methyltransferase". Journal of Molecular Biology 221 (2): 431–440. doi:10.1016/0022-2836(91)80064-2. PMID 1833555.
- Pósfai J, Bhagwat AS, Roberts RJ (December 1988). "Sequence motifs specific for cytosine methyltransferases". Gene 74 (1): 261–5. doi:10.1016/0378-1119(88)90299-5. PMID 3248729.
- Kumar S, Cheng X, Klimasauskas S, Mi S, Posfai J, Roberts RJ, Wilson GG (January 1994). "The DNA (cytosine-5) methyltransferases". Nucleic Acids Res. 22 (1): 1–10. doi:10.1093/nar/22.1.1. PMC 307737. PMID 8127644.
- Lauster R, Trautner TA, Noyer-Weidner M (March 1989). "Cytosine-specific type II DNA methyltransferases. A conserved enzyme core with variable target-recognizing domains". J. Mol. Biol. 206 (2): 305–12. doi:10.1016/0022-2836(89)90480-4. PMID 2716049.
- Cheng X (February 1995). "DNA modification by methyltransferases". Curr. Opin. Struct. Biol. 5 (1): 4–10. doi:10.1016/0959-440X(95)80003-J. PMID 7773746.
- Cheng X, Kumar S, Posfai J, Pflugrath JW, Roberts RJ (July 1993). "Crystal structure of the HhaI DNA methyltransferase complexed with S-adenosyl-L-methionine". Cell 74 (2): 299–307. doi:10.1016/0092-8674(93)90421-L. PMID 8343957.
- "DNMT1". Gene Symbol Report. HUGO Gene Nomenclature Committee. Retrieved 2012-09-27.
- "DNMT3A". Gene Symbol Report. HUGO Gene Nomenclature Committee. Retrieved 2012-09-27.
- "DNMT3B". Gene Symbol Report. HUGO Gene Nomenclature Committee. Retrieved 2012-09-27.
- "DNMT3L". Gene Symbol Report. HUGO Gene Nomenclature Committee. Retrieved 2012-09-27.
- Kho MR, Baker DJ, Laayoun A, Smith SS (1998). "Stalling of Human DNA (Cytosine-5) Methyltransferase at Single Strand Conformers form a Site of Dynamic Mutation". Journal of Molecular Biology 275 (1): 67–79. doi:10.1006/jmbi.1997.1430. PMID 9451440.
- Smith SS, Kaplan BE, Sowers LC, Newman EM (1992). "Mechanism of human methyl-directed DNA methyltransferase and the fidelity of cytosine methylation". Proceedings of the National Academy of Sciences of the United States of America 89 (10): 4748–4744. doi:10.1073/pnas.89.10.4744. PMC 49160. PMID 1584813.
- Jair KW, Bachman KE, Suzuki H, Ting AH, Rhee I, Yen RW, Baylin SB, Schuebel KE (2006). "De novo CpG Island Methylation in Human Cancer Cells". Cancer Research 69 (2): 682–692. doi:10.1158/0008-5472.CAN-05-1980. PMID 16423997.
- Ting AH, Jair KW, Schuebel KE, Baylin SB (2006). "Differential Requirement for DNA Methyltransferse 1 In Maintianing Cancer Cell Gene Promoter Hypermethylation". Cancer Research 66 (2): 729–735. doi:10.1158/0008-5472.CAN-05-1537. PMID 16424002.
- Li E, Bestor TH, Jaenisch R (1992). "Targeted Mutation of the DNA Methyltransferase Gene Results in Embryonic Lethality". Cell 69 (6): 915–926. doi:10.1016/0092-8674(92)90611-F. PMID 1606615.
- Goll MG, Kirpekar F, Maggert KA, Yoder JA, Hsieh CL, Zhang X, Golic KG, Jacobsen SE, Bestor TH (2006). "Methylation of tRNAAsp by the DNA Methyltransferase Homolog Dnmt2". Science 311 (5759): 395–398. doi:10.1126/science.1120976. PMID 16424344.
- "TRDMT1 tRNA aspartic acid methyltransferase 1 (Homo sapiens)". Entrez Gene. NCBI. 2010-11-01. Retrieved 2010-11-07.
- Mack GS (2010). "To selectivity and beyond". Nat. Biotechnol. 28 (12): 1259–66. doi:10.1038/nbt.1724. PMID 21139608.
- Smith SS (1994). "Biological implications of the mechanism of action of human DNA (cytosine-5)methyltransferase". Prog. Nucleic Acid Res. Mol. Biol. 49: 65–111. PMID 7863011.
- Pradhan S, Esteve PO (2003). "Mammalian DNA (cytosine-5) methyltransferases and their expression". Clin. Immunol. 109 (1): 6–16. doi:10.1016/S1521-6616(03)00204-3. PMID 14585271.
- Goll MG, Bestor TH (2005). "Eukaryotic cytosine methyltransferases". Annu. Rev. Biochem. 74: 481–514. doi:10.1146/annurev.biochem.74.010904.153721. PMID 15952895.
- Svedruzić ZM (2008). "Mammalian cytosine DNA methyltransferase Dnmt1: enzymatic mechanism, novel mechanism-based inhibitors, and RNA-directed DNA methylation". Curr. Med. Chem. 15 (1): 92–106. doi:10.2174/092986708783330700. PMID 18220765.
- Information about DNA methyltransferases and DNA methylation at epigeneticstation.com
- Data for a DNA methyltransferase (DNMT) Antibody
- DNA Modification Methyltransferases at the US National Library of Medicine Medical Subject Headings (MeSH)
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
HsdM N-terminal domain Provide feedback
This domain is found at the N-terminus of the methylase subunit of Type I DNA methyltransferases. This domain family is found in bacteria and archaea, and is typically between 123 and 138 amino acids in length. The family is found in association with PF02384. Mutations in this region of EcoKI methyltransferase P08957 abolish the normally strong preference of this system for methylating hemimethylated substrate . The structure of this domain has been shown to be all alpha-helical.
This tab holds annotation information from the InterPro database.
InterPro entry IPR022749
This domain is found at the N terminus of the methylase subunit of Type I DNA methyltransferases. This domain is found in bacteria and archaea, and is typically between 123 and 138 amino acids in length. It is found in association with . Mutations in this region of EcoKI methyltransferase SWISSPROT abolish the normally strong preference of this system for methylating hemimethylated substrate [PUBMED:1833555]. The structure of this domain has been shown to be all alpha-helical.
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Seed source:||PFAM-B_2036 (release 23.0)|
|Author:||Bateman A, Assefa S, Coggill P|
|Number in seed:||67|
|Number in full:||1576|
|Average length of the domain:||134.20 aa|
|Average identity of full alignment:||19 %|
|Average coverage of the sequence by the domain:||24.51 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||5|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
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There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the HsdM_N domain has been found. There are 13 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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