The structure of human EXD2 reveals a chimeric 3' to 5' exonuclease domain that discriminates substrates via metal coordination.
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Authors
Park, Jumi
Lee, Song-Yi
Jeong, Hanbin
Kang, Myeong-Gyun
Van Haute, Lindsey
Seo, Jeong Kon
Jun, Youngsoo
Myung, Kyungjae
Rhee, Hyun-Woo
Lee, Changwook
Publication Date
2019-05-25Journal Title
Nucleic Acids Research
ISSN
0305-1048
Publisher
Oxford University Press
Number
gkz4514
Language
eng
Type
Article
This Version
VoR
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Park, J., Lee, S., Jeong, H., Kang, M., Van Haute, L., Minczuk, M., Seo, J. K., et al. (2019). The structure of human EXD2 reveals a chimeric 3' to 5' exonuclease domain that discriminates substrates via metal coordination.. Nucleic Acids Research, (gkz4514)https://doi.org/10.1093/nar/gkz454
Abstract
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 α5-α7 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.
Sponsorship
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), funded by the Ministry of Health & Welfare, Republic of Korea [HI18C1395]; Institute for Basic Science [IBS-R022-D1]. Funding for open access charge: Cell Logistics Research Center, National Research Foundation of Korea [2016R1A5A1007318].
Funder references
MRC (MC_UU_00015/4)
Identifiers
External DOI: https://doi.org/10.1093/nar/gkz454
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293284
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Licence:
http://creativecommons.org/licenses/by-nc/4.0/