7r77

Cryo-EM structure of DNMT5 binary complex with hemimethylated DNACryo-EM structure of DNMT5 binary complex with hemimethylated DNA

Structural highlights

7r77 is a 3 chain structure with sequence from Cryptococcus neoformans and Cryptococcus neoformans var. grubii H99. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DMT5_CRYNH ATP-dependent cytosine methylase that maintains DNA methylation by acting at hemimethylated palindromic 5'-CG-3' sites to produce symmetrically methylated DNA strands (PubMed:24630728, PubMed:31955845, PubMed:32437639). DNA methylation may play a role in transcriptional silencing, particularly at transposable elements (PubMed:24630728).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Epigenetic evolution occurs over million-year timescales in Cryptococcus neoformans and is mediated by DNMT5, the first maintenance type cytosine methyltransferase identified in the fungal or protist kingdoms, the first dependent on adenosine triphosphate (ATP), and the most hemimethyl-DNA-specific enzyme known. To understand these novel properties, we solved cryo-EM structures of CnDNMT5 in three states. These studies reveal an elaborate allosteric cascade in which hemimethylated DNA binding first activates the SNF2 ATPase domain by a large rigid body rotation while the target cytosine partially flips out of the DNA duplex. ATP binding then triggers striking structural reconfigurations of the methyltransferase catalytic pocket to enable cofactor binding, completion of base flipping, and catalysis. Bound unmethylated DNA does not open the catalytic pocket and is instead ejected upon ATP binding, driving high fidelity. This unprecedented chaperone-like, enzyme-remodeling role of the SNF2 ATPase domain illuminates how energy is used to enable faithful epigenetic memory.

Structural insights into DNMT5-mediated ATP-dependent high-fidelity epigenome maintenance.,Wang J, Catania S, Wang C, de la Cruz MJ, Rao B, Madhani HD, Patel DJ Mol Cell. 2022 Feb 16. pii: S1097-2765(22)00104-6. doi:, 10.1016/j.molcel.2022.01.028. PMID:35202575^[5]

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

References

↑ Huff JT, Zilberman D. Dnmt1-independent CG methylation contributes to nucleosome positioning in diverse eukaryotes. Cell. 2014 Mar 13;156(6):1286-1297. doi: 10.1016/j.cell.2014.01.029. PMID:24630728 doi:http://dx.doi.org/10.1016/j.cell.2014.01.029
↑ Catania S, Dumesic PA, Pimentel H, Nasif A, Stoddard CI, Burke JE, Diedrich JK, Cook S, Shea T, Geinger E, Lintner R, Yates JR 3rd, Hajkova P, Narlikar GJ, Cuomo CA, Pritchard JK, Madhani HD. Evolutionary Persistence of DNA Methylation for Millions of Years after Ancient Loss of a De Novo Methyltransferase. Cell. 2020 Jan 23;180(2):263-277.e20. doi: 10.1016/j.cell.2019.12.012. Epub 2020 , Jan 16. PMID:31955845 doi:http://dx.doi.org/10.1016/j.cell.2019.12.012
↑ Dumesic PA, Stoddard CI, Catania S, Narlikar GJ, Madhani HD. ATP Hydrolysis by the SNF2 Domain of Dnmt5 Is Coupled to Both Specific Recognition and Modification of Hemimethylated DNA. Mol Cell. 2020 Jul 2;79(1):127-139.e4. doi: 10.1016/j.molcel.2020.04.029. Epub, 2020 May 20. PMID:32437639 doi:http://dx.doi.org/10.1016/j.molcel.2020.04.029
↑ Huff JT, Zilberman D. Dnmt1-independent CG methylation contributes to nucleosome positioning in diverse eukaryotes. Cell. 2014 Mar 13;156(6):1286-1297. doi: 10.1016/j.cell.2014.01.029. PMID:24630728 doi:http://dx.doi.org/10.1016/j.cell.2014.01.029
↑ Wang J, Catania S, Wang C, de la Cruz MJ, Rao B, Madhani HD, Patel DJ. Structural insights into DNMT5-mediated ATP-dependent high-fidelity epigenome maintenance. Mol Cell. 2022 Feb 16. pii: S1097-2765(22)00104-6. doi:, 10.1016/j.molcel.2022.01.028. PMID:35202575 doi:http://dx.doi.org/10.1016/j.molcel.2022.01.028

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OCA

[1] Huff JT, Zilberman D. Dnmt1-independent CG methylation contributes to nucleosome positioning in diverse eukaryotes. Cell. 2014 Mar 13;156(6):1286-1297. doi: 10.1016/j.cell.2014.01.029. PMID:24630728 doi:http://dx.doi.org/10.1016/j.cell.2014.01.029

[2] Catania S, Dumesic PA, Pimentel H, Nasif A, Stoddard CI, Burke JE, Diedrich JK, Cook S, Shea T, Geinger E, Lintner R, Yates JR 3rd, Hajkova P, Narlikar GJ, Cuomo CA, Pritchard JK, Madhani HD. Evolutionary Persistence of DNA Methylation for Millions of Years after Ancient Loss of a De Novo Methyltransferase. Cell. 2020 Jan 23;180(2):263-277.e20. doi: 10.1016/j.cell.2019.12.012. Epub 2020 , Jan 16. PMID:31955845 doi:http://dx.doi.org/10.1016/j.cell.2019.12.012

[3] Dumesic PA, Stoddard CI, Catania S, Narlikar GJ, Madhani HD. ATP Hydrolysis by the SNF2 Domain of Dnmt5 Is Coupled to Both Specific Recognition and Modification of Hemimethylated DNA. Mol Cell. 2020 Jul 2;79(1):127-139.e4. doi: 10.1016/j.molcel.2020.04.029. Epub, 2020 May 20. PMID:32437639 doi:http://dx.doi.org/10.1016/j.molcel.2020.04.029

[4] Huff JT, Zilberman D. Dnmt1-independent CG methylation contributes to nucleosome positioning in diverse eukaryotes. Cell. 2014 Mar 13;156(6):1286-1297. doi: 10.1016/j.cell.2014.01.029. PMID:24630728 doi:http://dx.doi.org/10.1016/j.cell.2014.01.029

[5] Wang J, Catania S, Wang C, de la Cruz MJ, Rao B, Madhani HD, Patel DJ. Structural insights into DNMT5-mediated ATP-dependent high-fidelity epigenome maintenance. Mol Cell. 2022 Feb 16. pii: S1097-2765(22)00104-6. doi:, 10.1016/j.molcel.2022.01.028. PMID:35202575 doi:http://dx.doi.org/10.1016/j.molcel.2022.01.028

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