Journal
NUCLEIC ACIDS RESEARCH
Volume 47, Issue 13, Pages 7078-7093Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz454
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Funding
- Cell Logistics Research Center [2016R1A5A1007318]
- Basic Research Program, National Research Foundation of Korea [NRF-2019R1A2C3008463]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI18C1395]
- Institute for Basic Science [IBS-R022-D1]
- Cell Logistics Research Center, National Research Foundation of Korea [2016R1A5A1007318]
- MRC [MC_UU_00015/4] Funding Source: UKRI
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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 alpha 5-alpha 7 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.
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