A Unique DNA-binding Mode of African Swine Fever Virus AP Endonuclease

Overview

Journal Cell Discov

Date 2020 Mar 21

PMID 32194979

Citations 14

Authors

Yiqing Chen

Xi Chen

Qi Huang

Zhiwei Shao

Yanqing Gao

Yangyang Li

Chun Yang

Hehua Liu

Jixi Li

Qiyao Wang

Jinbiao Ma

Yong-Zhen Zhang

Yijun Gu

Jianhua Gan

Affiliations

Soon will be listed here.

Abstract

African swine fever virus (ASFV) is highly contagious and can cause lethal disease in pigs. ASFV is primarily replicated in the cytoplasm of pig macrophages, which is oxidative and caused constant damage to ASFV genome. ASFV AP endonuclease (AP) catalyzes DNA cleavage reaction at the abasic site and is a key enzyme of ASFV base excision repair (BER) system. Although it plays an essential role in ASFV survival in host cells, the basis underlying substrate binding and cleavage by AP remains unclear. Here, we reported the structural and functional studies of AP, showing that AP adopts a novel DNA-binding mode distinct from other APs. AP possesses many unique structural features, including one narrower nucleotide-binding pocket at the active site, the C16-C20 disulfide bond-containing region, and histidine-rich loop. As indicated by our mutagenesis, in vitro binding and cleavage assays, these features are important for AP to suit the acidic and oxidative environment. Owing to their functional importance, these unique features could serve as targets for designing small molecule inhibitors that could disrupt the repair process of ASFV genome and help fight against this deadly virus in the future.

Citing Articles

Structures of African swine fever virus topoisomerase complex and their implications.

Yang J, Shao Z, Zhao X, Zhang W, Zhang Y, Li L Nat Commun. 2024; 15(1):6484.

PMID: 39090127 PMC: 11294524. DOI: 10.1038/s41467-024-50981-y.

identification of multi-target inhibitors from medicinal fungal metabolites against the base excision repair pathway proteins of African swine fever virus.

Macalalad M, Orosco F RSC Adv. 2024; 14(14):10039-10055.

PMID: 38533097 PMC: 10964135. DOI: 10.1039/d4ra00819g.

A unified view on enzyme catalysis by cryo-EM study of a DNA topoisomerase.

Chang C, Wang S, Wang C, Pang A, Yang C, Chang Y Commun Chem. 2024; 7(1):45.

PMID: 38418525 PMC: 10901890. DOI: 10.1038/s42004-024-01129-y.

Structures and implications of the C962R protein of African swine fever virus.

Shao Z, Su S, Yang J, Zhang W, Gao Y, Zhao X Nucleic Acids Res. 2023; 51(17):9475-9490.

PMID: 37587714 PMC: 10516667. DOI: 10.1093/nar/gkad677.

Structural and functional studies of PCNA from African swine fever virus.

Shao Z, Yang J, Gao Y, Zhang Y, Zhao X, Shao Q J Virol. 2023; 97(8):e0074823.

PMID: 37534905 PMC: 10506467. DOI: 10.1128/jvi.00748-23.

References

Zhang W, Xu Y, Yan M, Li S, Wang H, Yang H . Crystal structure of the apurinic/apyrimidinic endonuclease IV from Mycobacterium tuberculosis. Biochem Biophys Res Commun. 2018; 498(1):111-118. DOI: 10.1016/j.bbrc.2018.02.181. View

Zhou X, Li N, Luo Y, Liu Y, Miao F, Chen T . Emergence of African Swine Fever in China, 2018. Transbound Emerg Dis. 2018; 65(6):1482-1484. DOI: 10.1111/tbed.12989. View

Wu W, Su M, Wu J, Kumar S, Lim L, Wang C . How a low-fidelity DNA polymerase chooses non-Watson-Crick from Watson-Crick incorporation. J Am Chem Soc. 2014; 136(13):4927-37. DOI: 10.1021/ja4102375. View

Hakim M, Fass D . Dimer interface migration in a viral sulfhydryl oxidase. J Mol Biol. 2009; 391(4):758-68. DOI: 10.1016/j.jmb.2009.06.070. View

Bastos A, Penrith M, Cruciere C, Edrich J, Hutchings G, Roger F . Genotyping field strains of African swine fever virus by partial p72 gene characterisation. Arch Virol. 2003; 148(4):693-706. DOI: 10.1007/s00705-002-0946-8. View

Asano R, Ishikawa H, Nakane S, Nakagawa N, Kuramitsu S, Masui R . An additional C-terminal loop in endonuclease IV, an apurinic/apyrimidinic endonuclease, controls binding affinity to DNA. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 3):149-55. DOI: 10.1107/S0907444910052479. View

Canton J, Khezri R, Glogauer M, Grinstein S . Contrasting phagosome pH regulation and maturation in human M1 and M2 macrophages. Mol Biol Cell. 2014; 25(21):3330-41. PMC: 4214780. DOI: 10.1091/mbc.E14-05-0967. View

Chen Y, Liu H, Yang C, Gao Y, Yu X, Chen X . Structure of the error-prone DNA ligase of African swine fever virus identifies critical active site residues. Nat Commun. 2019; 10(1):387. PMC: 6344480. DOI: 10.1038/s41467-019-08296-w. View

Adams P, Grosse-Kunstleve R, Hung L, Ioerger T, McCoy A, Moriarty N . PHENIX: building new software for automated crystallographic structure determination. Acta Crystallogr D Biol Crystallogr. 2002; 58(Pt 11):1948-54. DOI: 10.1107/s0907444902016657. View

10.

Tseng H, Shum D, Bhinder B, Escobar S, Veomett N, Tomkinson A . A high-throughput scintillation proximity-based assay for human DNA ligase IV. Assay Drug Dev Technol. 2011; 10(3):235-49. PMC: 3374410. DOI: 10.1089/adt.2011.0404. View

11.

Redrejo-Rodriguez M, Garcia-Escudero R, Yanez-Munoz R, Salas M, Salas J . African swine fever virus protein pE296R is a DNA repair apurinic/apyrimidinic endonuclease required for virus growth in swine macrophages. J Virol. 2006; 80(10):4847-57. PMC: 1472066. DOI: 10.1128/JVI.80.10.4847-4857.2006. View

12.

Lord C, Ashworth A . Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol. 2008; 8(4):363-9. DOI: 10.1016/j.coph.2008.06.016. View

13.

Zhong S, Chen X, Zhu X, Dziegielewska B, Bachman K, Ellenberger T . Identification and validation of human DNA ligase inhibitors using computer-aided drug design. J Med Chem. 2008; 51(15):4553-62. PMC: 2788817. DOI: 10.1021/jm8001668. View

14.

Garcin E, Hosfield D, Desai S, Haas B, Bjoras M, Cunningham R . DNA apurinic-apyrimidinic site binding and excision by endonuclease IV. Nat Struct Mol Biol. 2008; 15(5):515-22. DOI: 10.1038/nsmb.1414. View

15.

Forman H, Torres M . Redox signaling in macrophages. Mol Aspects Med. 2001; 22(4-5):189-216. DOI: 10.1016/s0098-2997(01)00010-3. View

16.

Achenbach J, Gallardo C, Nieto-Pelegrin E, Rivera-Arroyo B, Degefa-Negi T, Arias M . Identification of a New Genotype of African Swine Fever Virus in Domestic Pigs from Ethiopia. Transbound Emerg Dis. 2016; 64(5):1393-1404. DOI: 10.1111/tbed.12511. View

17.

Terwilliger T, Adams P, Read R, McCoy A, Moriarty N, Grosse-Kunstleve R . Decision-making in structure solution using Bayesian estimates of map quality: the PHENIX AutoSol wizard. Acta Crystallogr D Biol Crystallogr. 2009; 65(Pt 6):582-601. PMC: 2685735. DOI: 10.1107/S0907444909012098. View

18.

Murshudov G, Skubak P, Lebedev A, Pannu N, Steiner R, Nicholls R . REFMAC5 for the refinement of macromolecular crystal structures. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):355-67. PMC: 3069751. DOI: 10.1107/S0907444911001314. View

19.

Giacovazzo C, Siliqi D . Phasing via SAD/MAD data: the method of the joint probability distribution functions. Acta Crystallogr D Biol Crystallogr. 2003; 60(Pt 1):73-82. DOI: 10.1107/s0907444903022406. View

20.

Costard S, Mur L, Lubroth J, Sanchez-Vizcaino J, Pfeiffer D . Epidemiology of African swine fever virus. Virus Res. 2012; 173(1):191-7. DOI: 10.1016/j.virusres.2012.10.030. View