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Nucleic Acids Res., Published: 25 May 2019 | https://doi.org/10.1093/nar/gkz454 The structure of human EXD2 reveals a chimeric 3′ to 5′ exonuclease domain that discriminates substrates via metal coordination

Jumi Park^1,7,†, Song-Yi Lee^2,3,†, Hanbin Jeong^1,7, Myeong-Gyun Kang², Lindsey Van Haute⁴, Michal Minczuk⁴, Jeong Kon Seo⁵, Youngsoo Jun^6,7, Kyungjae Myung^1,8, Hyun-Woo Rhee^3,*and Changwook Lee^1,7,8,*

¹ Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, 50 UNIST-gil, Ulsan 44919, Republic of Korea, ² Department of Chemistry, Ulsan National Institute of Science and Technology, 50 UNIST-gil, Ulsan 44919, Republic of Korea,³ Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea,⁴ MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK, ⁵ UNIST Central Research Facilities (UCRF), Ulsan National Institute of Science and Technology, 50 UNIST-gil, Ulsan 44919, Republic of Korea, ⁶ School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea, ⁷Cell Logistics Research Center, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea and ⁸ Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea

^*To whom correspondence should be addressed.

^†The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors.

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.

논문정보

형식Research article
게재일2019년 05월 (BRIC 등록일 2019-06-05)
연구진국내(교신)+국외 연구진
분야 생명과학 > 생화학

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