6k1c

From Proteopedia

Crystal structure of EXD2 exonuclease domain soaked in Mg and dGMP

Structural highlights

6k1c is a 2 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 2.45Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

EXD2_HUMAN Exonuclease required for double-strand breaks resection and efficient homologous recombination. Plays a key role in controlling the initial steps of chromosomal break repair, it is recruited to chromatin in a damage-dependent manner and functionally interacts with the MRN complex to accelerate resection through its 3'-5' exonuclease activity, which efficiently processes double-stranded DNA substrates containing nicks.^[1] ^[2]

Publication Abstract from PubMed

EXD2 (3'-5' exonuclease domain-containing protein 2) is an essential protein with a conserved DEDDy superfamily 3'-5' exonuclease domain. Recent research suggests that EXD2 has two potential functions: as a component of the DNA double-strand break repair machinery and as a ribonuclease for the regulation of mitochondrial translation. Herein, electron microscope imaging analysis and proximity labeling revealed that EXD2 is anchored to the mitochondrial outer membrane through a conserved N-terminal transmembrane domain, while the C-terminal region is cytosolic. Crystal structures of the exonuclease domain in complex with Mn2+/Mg2+ revealed a domain-swapped dimer in which the central alpha5-alpha7 helices are mutually crossed over, resulting in chimeric active sites. Additionally, the C-terminal segments absent in other DnaQ family exonucleases enclose the central chimeric active sites. Combined structural and biochemical analyses demonstrated that the unusual dimeric organization stabilizes the active site, facilitates discrimination between DNA and RNA substrates based on divalent cation coordination and generates a positively charged groove that binds substrates.

The structure of human EXD2 reveals a chimeric 3' to 5' exonuclease domain that discriminates substrates via metal coordination.,Park J, Lee SY, Jeong H, Kang MG, Van Haute L, Minczuk M, Seo JK, Jun Y, Myung K, Rhee HW, Lee C Nucleic Acids Res. 2019 Jul 26;47(13):7078-7093. doi: 10.1093/nar/gkz454. PMID:31127291^[3]

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

References

↑ Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiacovo MP, Elledge SJ. A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol Cell. 2010 Jul 9;39(1):36-47. doi: 10.1016/j.molcel.2010.06.023. PMID:20603073 doi:http://dx.doi.org/10.1016/j.molcel.2010.06.023
↑ Broderick R, Nieminuszczy J, Baddock HT, Deshpande R, Gileadi O, Paull TT, McHugh PJ, Niedzwiedz W. EXD2 promotes homologous recombination by facilitating DNA end resection. Nat Cell Biol. 2016 Mar;18(3):271-280. doi: 10.1038/ncb3303. Epub 2016 Jan 25. PMID:26807646 doi:http://dx.doi.org/10.1038/ncb3303
↑ Park J, Lee SY, Jeong H, Kang MG, Van Haute L, Minczuk M, Seo JK, Jun Y, Myung K, Rhee HW, Lee C. The structure of human EXD2 reveals a chimeric 3' to 5' exonuclease domain that discriminates substrates via metal coordination. Nucleic Acids Res. 2019 Jul 26;47(13):7078-7093. doi: 10.1093/nar/gkz454. PMID:31127291 doi:http://dx.doi.org/10.1093/nar/gkz454