2moe

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Solution structure of MBD4 methyl-cytosine binding domain bound to methylated DNA

Structural highlights

2moe is a 3 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Ligands:5CM
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MBD4_HUMAN Mismatch-specific DNA N-glycosylase involved in DNA repair. Has thymine glycosylase activity and is specific for G:T mismatches within methylated and unmethylated CpG sites. Can also remove uracil or 5-fluorouracil in G:U mismatches. Has no lyase activity. Was first identified as methyl-CpG-binding protein.[1] [2]

Publication Abstract from PubMed

Unlike other members of the methyl-cytosine binding domain (MBD) family, MBD4 serves as a potent DNA glycosylase in DNA mismatch repair specifically targeting mCpG/TpG mismatches arising from spontaneous deamination of methyl-cytosine. The protein contains an N-terminal MBD (MBD4MBD) and a C-terminal glycosylase domain (MBD4GD) separated by a long linker. This arrangement suggests that the MBD4MBD either directly augments enzymatic catalysis by the MBD4GD or targets the protein to regions enriched for mCpG/TpG mismatches. Here we present structural and dynamic studies of MBD4MBD bound to dsDNA. We show that MBD4MBD binds with a modest preference for mCpG as compared to mismatch, unmethylated and hydroxymethylated DNA. We find that while MBD4MBD exhibits slow exchange between molecules of DNA (intermolecular exchange), the domain exhibits fast exchange between two sites in the same molecule of dsDNA (intramolecular exchange). Introducing a single-strand defect between binding sites does not greatly reduce the intramolecular exchange rate, consistent with a local hopping mechanism for moving along the DNA. These results support a model in which the MBD4MBD4 targets the intact protein to (m)CpG islands and promotes scanning by rapidly exchanging between successive mCpG sites which facilitates repair of nearby mCpG/TpG mismatches by the glycosylase domain.

Solution structure and intramolecular exchange of methyl-cytosine binding domain protein 4 (MBD4) on DNA suggests a mechanism to scan for mCpG/TpG mismatches.,Walavalkar NM, Cramer JM, Buchwald WA, Scarsdale JN, Williams DC Jr Nucleic Acids Res. 2014;42(17):11218-32. doi: 10.1093/nar/gku782. Epub 2014 Sep, 2. PMID:25183517[3]

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

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Citations
6 reviews cite this structure
Role of base excision repair in maintaining the genetic and epigenetic integrity of CpG sites.
Bellacosa et al. (2015)
5 more
10 other articles
No citations found

See Also

References

  1. ↑ Bellacosa A, Cicchillitti L, Schepis F, Riccio A, Yeung AT, Matsumoto Y, Golemis EA, Genuardi M, Neri G. MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3969-74. PMID:10097147
  2. ↑ Petronzelli F, Riccio A, Markham GD, Seeholzer SH, Stoerker J, Genuardi M, Yeung AT, Matsumoto Y, Bellacosa A. Biphasic kinetics of the human DNA repair protein MED1 (MBD4), a mismatch-specific DNA N-glycosylase. J Biol Chem. 2000 Oct 20;275(42):32422-9. PMID:10930409 doi:10.1074/jbc.M004535200
  3. ↑ Walavalkar NM, Cramer JM, Buchwald WA, Scarsdale JN, Williams DC Jr. Solution structure and intramolecular exchange of methyl-cytosine binding domain protein 4 (MBD4) on DNA suggests a mechanism to scan for mCpG/TpG mismatches. Nucleic Acids Res. 2014;42(17):11218-32. doi: 10.1093/nar/gku782. Epub 2014 Sep, 2. PMID:25183517 doi:http://dx.doi.org/10.1093/nar/gku782

Contents


PDB ID 2moe

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