FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Journal of virology2016; 91(1); doi: 10.1128/JVI.01309-16

Structural Biology of the Arterivirus nsp11 Endoribonucleases.

Abstract: Endoribonuclease (NendoU) is unique and conserved as a major genetic marker in nidoviruses that infect vertebrate hosts. Arterivirus nonstructural protein 11 (nsp11) was shown to have NendoU activity and play essential roles in the viral life cycle. Here, we report three crystal structures of porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus (EAV) nsp11 mutants. The structures of arterivirus nsp11 contain two conserved compact domains: the N-terminal domain (NTD) and C-terminal domain (CTD). The structures of PRRSV and EAV endoribonucleases are similar and conserved in the arterivirus, but they are greatly different from that of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoV), representing important human pathogens in the Nidovirales order. The catalytic center of NendoU activity is located in the CTD, where a positively charged groove is next to the key catalytic residues conserved in nidoviruses. Although the NTD is nearly identical, the catalytic region of the arterivirus nsp11 family proteins is remarkably flexible, and the oligomerization may be concentration dependent. In summary, our structures provide new insight into this key multifunctional NendoU family of proteins and lay a foundation for better understanding of the molecular mechanism and antiviral drug development. Objective: Porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus are two major members of the arterivirus family. PRRSV, a leading swine pathogen, causes reproductive failure in breeding stock and respiratory tract illness in young pigs. Due to the lack of a suitable vaccine or effective drug treatment and the quick spread of these viruses, infected animals either die quickly or must be culled. PRRSV costs the swine industry around $644 million annually in the United States and almost €1.5 billion in Europe every year. To find a way to combat these viruses, we focused on the essential viral nonstructural protein 11 (nsp11). nsp11 is associated with multiple functions, such as RNA processing and suppression of the infected host innate immunity system. The three structures solved in this study provide new insight into the molecular mechanisms of this crucial protein family and will benefit the development of new treatments against these deadly viruses.
Copyright © 2016 American Society for Microbiology.
Get Full Text
Publication Date: 2016-12-16 PubMed ID: 27795409PubMed Central: PMC5165224DOI: 10.1128/JVI.01309-16Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article presents the crystal structures of nonstructural protein 11 (nsp11) which plays significant roles in the life cycle of Arteriviruses. The findings of the study could pave the way for understanding the functionality of this protein family and aid in the development of treatments for viruses such as the porcine reproductive and respiratory syndrome virus and equine arteritis virus.

Understanding the Non-Structural Protein in Arteriviruses

  • The study is centered on the endoribonuclease (NendoU), a significant genetic marker in nidoviruses. In particular, it focuses on the Arterivirus nonstructural protein 11 (nsp11) which exhibits NendoU activity and plays crucial roles in viral reproduction.
  • The team examined three crystal structures of nsp11, derived from mutants of the porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus (EAV). These viruses are significant members of the arterivirus family and are known for causing severe damages in livestock.
  • The extracted structures have two conserved compact domains: the N-terminal domain (NTD) and C-terminal domain (CTD), both of which maintain their similarity and conservatism in the arterivirus but show remarkable difference from those of SARS and MERS coronaviruses.

The Role of nsp11 in the Viral Life Cycle

  • The CTD contains the catalytic center of NendoU activity, which is crucial for reproduction. Adjacent to it is a positively charged groove, another key feature in nidoviruses.
  • Interestingly, despite the nearly identical NTD, the nsp11’s catalytic region is highly flexible, and the protein’s tendency to form multi-unit structures or oligomerization appears to be dependent on concentration.
  • nsp11 is associated with multiple functions in the virus life cycle, like RNA processing and suppression of the host’s innate immunity system. These aspects make nsp11 a vital target for finding treatments against these deadly viruses.

Implications of the Study

  • The findings provide a foundation for better understanding the functionalities and molecular mechanisms of the NendoU protein family.
  • The knowledge derived from the crystal structures of nsp11 could be pivotal in the development of antiviral drugs, given the significant damage caused by the viruses in livestock, particularly swine leading to massive economic loss.

Cite This Article

APA
Zhang M, Li X, Deng Z, Chen Z, Liu Y, Gao Y, Wu W, Chen Z. (2016). Structural Biology of the Arterivirus nsp11 Endoribonucleases. J Virol, 91(1). https://doi.org/10.1128/JVI.01309-16

Publication

Journal of virology
ISSN: 1098-5514
NlmUniqueID: 0113724
Country: United States
Language: English
Volume: 91
Issue: 1

Researcher Affiliations

Zhang, Manfeng
  • Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China.
  • State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
Li, Xiaorong
  • State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
Deng, Zengqin
  • State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
Chen, Zhenhang
  • State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
Liu, Yang
  • State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
Gao, Yina
  • State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
Wu, Wei
  • State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
Chen, Zhongzhou
  • Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China chenzhongzhou@cau.edu.cn.
  • State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.

MeSH Terms

  • Amino Acid Sequence
  • Catalytic Domain
  • Conserved Sequence
  • Crystallography, X-Ray
  • Endoribonucleases / chemistry
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Equartevirus / chemistry
  • Equartevirus / enzymology
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Middle East Respiratory Syndrome Coronavirus / chemistry
  • Middle East Respiratory Syndrome Coronavirus / genetics
  • Middle East Respiratory Syndrome Coronavirus / metabolism
  • Models, Molecular
  • Mutation
  • Porcine respiratory and reproductive syndrome virus / chemistry
  • Porcine respiratory and reproductive syndrome virus / enzymology
  • Protein Domains
  • Protein Multimerization
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Severe acute respiratory syndrome-related coronavirus / chemistry
  • Severe acute respiratory syndrome-related coronavirus / genetics
  • Severe acute respiratory syndrome-related coronavirus / metabolism
  • Sequence Alignment
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism

References

This article includes 37 references
  1. Gorbalenya AE, Enjuanes L, Ziebuhr J, Snijder EJ. Nidovirales: evolving the largest RNA virus genome.. Virus Res 117:17–37.
    doi: 10.1016/j.virusres.2006.01.017pmc: PMC7114179pubmed: 16503362google scholar: lookup
  2. Snijder EJ, Meulenberg JJ. The molecular biology of arteriviruses.. J Gen Virol 79:961–979.
    doi: 10.1099/0022-1317-79-5-961pubmed: 9603311google scholar: lookup
  3. Selmi C, Ansari AA, Invernizzi P, Podda M, Gershwin ME. The search for a practical approach to emerging diseases: the case of severe acute respiratory syndrome (SARS).. Dev Immunol 9:113–117.
    doi: 10.1080/1044667031000137575pmc: PMC2276106pubmed: 12885151google scholar: lookup
  4. Li Y, Zhou L, Zhang J, Ge X, Zhou R, Zheng H, Geng G, Guo X, Yang H. Nsp9 and Nsp10 contribute to the fatal virulence of highly pathogenic porcine reproductive and respiratory syndrome virus emerging in China.. PLoS Pathog 10:e1004216.
    doi: 10.1371/journal.ppat.1004216pmc: PMC4081738pubmed: 24992286google scholar: lookup
  5. den Boon JA, Snijder EJ, Chirnside ED, de Vries AA, Horzinek MC, Spaan WJ. Equine arteritis virus is not a togavirus but belongs to the coronaviruslike superfamily.. J Virol 65:2910–2920.
    pmc: PMC240924pubmed: 1851863
  6. Deng Z, Lehmann KC, Li X, Feng C, Wang G, Zhang Q, Qi X, Yu L, Zhang X, Feng W, Wu W, Gong P, Tao Y, Posthuma CC, Snijder EJ, Gorbalenya AE, Chen Z. Structural basis for the regulatory function of a complex zinc-binding domain in a replicative arterivirus helicase resembling a nonsense-mediated mRNA decay helicase.. Nucleic Acids Res 42:3464–3477.
    doi: 10.1093/nar/gkt1310pmc: PMC3950703pubmed: 24369429google scholar: lookup
  7. Thaa B, Kabatek A, Zevenhoven-Dobbe JC, Snijder EJ, Herrmann A, Veit M. Myristoylation of the arterivirus E protein: the fatty acid modification is not essential for membrane association but contributes significantly to virus infectivity.. J Gen Virol 90:2704–2712.
    doi: 10.1099/vir.0.011957-0pubmed: 19656967google scholar: lookup
  8. Li Y, Tas A, Sun Z, Snijder EJ, Fang Y. Proteolytic processing of the porcine reproductive and respiratory syndrome virus replicase.. Virus Res 202:48–59.
    doi: 10.1016/j.virusres.2014.12.027pubmed: 25557977google scholar: lookup
  9. Snijder EJ, Kikkert M, Fang Y. Arterivirus molecular biology and pathogenesis.. J Gen Virol 94:2141–2163.
    doi: 10.1099/vir.0.056341-0pubmed: 23939974google scholar: lookup
  10. Nga PT, Parquet Mdel C, Lauber C, Parida M, Nabeshima T, Yu F, Thuy NT, Inoue S, Ito T, Okamoto K, Ichinose A, Snijder EJ, Morita K, Gorbalenya AE. Discovery of the first insect nidovirus, a missing evolutionary link in the emergence of the largest RNA virus genomes.. PLoS Pathog 7:e1002215.
    doi: 10.1371/journal.ppat.1002215pmc: PMC3169540pubmed: 21931546google scholar: lookup
  11. Nedialkova DD, Ulferts R, van den Born E, Lauber C, Gorbalenya AE, Ziebuhr J, Snijder EJ. Biochemical characterization of arterivirus nonstructural protein 11 reveals the nidovirus-wide conservation of a replicative endoribonuclease.. J Virol 83:5671–5682.
    doi: 10.1128/JVI.00261-09pmc: PMC2681944pubmed: 19297500google scholar: lookup
  12. Posthuma CC, Nedialkova DD, Zevenhoven-Dobbe JC, Blokhuis JH, Gorbalenya AE, Snijder EJ. Site-directed mutagenesis of the Nidovirus replicative endoribonuclease NendoU exerts pleiotropic effects on the arterivirus life cycle.. J Virol 80:1653–1661.
    doi: 10.1128/JVI.80.4.1653-1661.2006pmc: PMC1367138pubmed: 16439522google scholar: lookup
  13. Ricagno S, Egloff MP, Ulferts R, Coutard B, Nurizzo D, Campanacci V, Cambillau C, Ziebuhr J, Canard B. Crystal structure and mechanistic determinants of SARS coronavirus nonstructural protein 15 define an endoribonuclease family.. Proc Natl Acad Sci U S A 103:11892–11897.
    doi: 10.1073/pnas.0601708103pmc: PMC2131687pubmed: 16882730google scholar: lookup
  14. Bhardwaj K, Palaninathan S, Alcantara JM, Yi LL, Guarino L, Sacchettini JC, Kao CC. Structural and functional analyses of the severe acute respiratory syndrome coronavirus endoribonuclease Nsp15.. J Biol Chem 283:3655–3664.
    doi: 10.1074/jbc.M708375200pmc: PMC8740563pubmed: 18045871google scholar: lookup
  15. He Q, Li Y, Zhou L, Ge XN, Guo X, Yang HC. Both Nsp1 beta and Nsp11 are responsible for differential TNF-alpha production induced by porcine reproductive and respiratory syndrome virus strains with different pathogenicity in vitro.. Virus Res 201:32–40.
    doi: 10.1016/j.virusres.2015.02.014pubmed: 25708177google scholar: lookup
  16. Beura LK, Sarkar SN, Kwon B, Subramaniam S, Jones C, Pattnaik AK, Osorio FA. Porcine reproductive and respiratory syndrome virus nonstructural protein 1beta modulates host innate immune response by antagonizing IRF3 activation.. J Virol 84:1574–1584.
    doi: 10.1128/JVI.01326-09pmc: PMC2812326pubmed: 19923190google scholar: lookup
  17. Sun Y, Li D, Giri S, Prasanth SG, Yoo D. Differential host cell gene expression and regulation of cell cycle progression by nonstructural protein 11 of porcine reproductive and respiratory syndrome virus.. Biomed Res Int 2014:430508.
    pmc: PMC3955671pubmed: 24719865
  18. Shi XB, Wang L, Li XW, Zhang GP, Guo JQ, Zhao D, Chai SJ, Deng RG. Endoribonuclease activities of porcine reproductive and respiratory syndrome virus nsp11 was essential for nsp11 to inhibit IFN-beta induction.. Mol Immunol 48:1568–1572.
    doi: 10.1016/j.molimm.2011.03.004pmc: PMC7112683pubmed: 21481939google scholar: lookup
  19. Wang D, Fan J, Fang L, Luo R, Ouyang H, Ouyang C, Zhang H, Chen H, Li K, Xiao S. The nonstructural protein 11 of porcine reproductive and respiratory syndrome virus inhibits NF-kappaB signaling by means of its deubiquitinating activity.. Mol Immunol 68:357–366.
    doi: 10.1016/j.molimm.2015.08.011pmc: PMC7112538pubmed: 26342881google scholar: lookup
  20. Holm L, Rosenstrom P. Dali server: conservation mapping in 3D.. Nucleic Acids Res 38:W545–W549.
    doi: 10.1093/nar/gkq366pmc: PMC2896194pubmed: 20457744google scholar: lookup
  21. Joseph JS, Saikatendu KS, Subramanian V, Neuman BW, Buchmeier MJ, Stevens RC, Kuhn P. Crystal structure of a monomeric form of severe acute respiratory syndrome coronavirus endonuclease nsp15 suggests a role for hexamerization as an allosteric switch.. J Virol 81:6700–6708.
    doi: 10.1128/JVI.02817-06pmc: PMC1900129pubmed: 17409150google scholar: lookup
  22. Yoo D, Song C, Sun Y, Du Y, Kim O, Liu HC. Modulation of host cell responses and evasion strategies for porcine reproductive and respiratory syndrome virus.. Virus Res 154:48–60.
    doi: 10.1016/j.virusres.2010.07.019pmc: PMC7114477pubmed: 20655963google scholar: lookup
  23. Shi Y, Li Y, Lei Y, Ye G, Shen Z, Sun L, Luo R, Wang D, Fu ZF, Xiao S, Peng G. A dimerization-dependent mechanism drives the endoribonuclease function of porcine reproductive and respiratory syndrome virus nsp11.. J Virol 90:4579–4592.
    doi: 10.1128/JVI.03065-15pmc: PMC4836315pubmed: 26912626google scholar: lookup
  24. Hengrung N, El Omari K, Serna Martin I, Vreede FT, Cusack S, Rambo RP, Vonrhein C, Bricogne G, Stuart DI, Grimes JM, Fodor E. Crystal structure of the RNA-dependent RNA polymerase from influenza C virus.. Nature 527:114–117.
    doi: 10.1038/nature15525pmc: PMC4783868pubmed: 26503046google scholar: lookup
  25. Ziebuhr J, Snijder EJ, Gorbalenya AE. Virus-encoded proteinases and proteolytic processing in the Nidovirales.. J Gen Virol 81:853–879.
    doi: 10.1099/0022-1317-81-4-853pubmed: 10725411google scholar: lookup
  26. Yan Y, Xin A, Zhu G, Huang H, Liu Q, Shao Z, Zang Y, Chen L, Sun Y, Gao H. Complete genome sequence of a novel natural recombinant porcine reproductive and respiratory syndrome virus isolated from a pig farm in Yunnan province, southwest China.. Genome Announc 1:e00003-12.
    doi: 10.1128/genomeA.00003-12pmc: PMC3569298pubmed: 23405309google scholar: lookup
  27. Otwinowski Z, Minor W. Processing of X-ray diffraction data collected in oscillation mode.. Methods Enzymol 276:307–326.
    doi: 10.1016/S0076-6879(97)76066-Xpubmed: 27754618google scholar: lookup
  28. Sheldrick GM. A short history of SHELX.. Acta Crystallogr A 64:112–122.
    doi: 10.1107/S0108767307043930pubmed: 18156677google scholar: lookup
  29. Terwilliger TC, Berendzen J. Automated MAD and MIR structure solution.. Acta Crystallogr D Biol Crystallogr 55:849–861.
    doi: 10.1107/S0907444999000839pmc: PMC2746121pubmed: 10089316google scholar: lookup
  30. Terwilliger TC, Grosse-Kunstleve RW, Afonine PV, Moriarty NW, Zwart PH, Hung LW, Read RJ, Adams PD. Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard.. Acta Crystallogr D Biol Crystallogr 64:61–69.
    doi: 10.1107/S090744490705024Xpmc: PMC2394820pubmed: 18094468google scholar: lookup
  31. Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of Coot.. Acta Crystallogr D Biol Crystallogr 66:486–501.
    doi: 10.1107/S0907444910007493pmc: PMC2852313pubmed: 20383002google scholar: lookup
  32. Murshudov GN, Skubak P, Lebedev AA, Pannu NS, Steiner RA, Nicholls RA, Winn MD, Long F, Vagin AA. REFMAC5 for the refinement of macromolecular crystal structures.. Acta Crystallogr D Biol Crystallogr 67:355–367.
    doi: 10.1107/S0907444911001314pmc: PMC3069751pubmed: 21460454google scholar: lookup
  33. Schrödinger LLC. PyMOL molecular graphics system, version 1.3.. .
  34. Zhang X, Zhang Q, Xin Q, Yu L, Wang Z, Wu W, Jiang L, Wang G, Tian W, Deng Z, Wang Y, Liu Z, Long J, Gong Z, Chen Z. Complex structures of the abscisic acid receptor PYL3/RCAR13 reveal a unique regulatory mechanism.. Structure 20:780–790.
    doi: 10.1016/j.str.2012.02.019pubmed: 22579247google scholar: lookup
  35. Hu Y, Chen Z, Fu Y, He Q, Jiang L, Zheng J, Gao Y, Mei P, Chen Z, Ren X. The amino-terminal structure of human fragile X mental retardation protein obtained using precipitant-immobilized imprinted polymers.. Nat Commun 6:6634.
    doi: 10.1038/ncomms7634pubmed: 25799254google scholar: lookup
  36. Nielsen SS, Toft KN, Snakenborg D, Jeppesen MG, Jacobsen JK, Vestergaard B, Kutter JP, Arleth L. BioXTAS RAW, a software program for high-throughput automated small-angle X-ray scattering data reduction and preliminary analysis.. J Appl Crystallogr 42:959–964.
    doi: 10.1107/S0021889809023863google scholar: lookup
  37. Pelikan M, Hura GL, Hammel M. Structure and flexibility within proteins as identified through small angle X-ray scattering.. Gen Physiol Biophys 28:174–189.
    doi: 10.4149/gpb_2009_02_174pmc: PMC3773563pubmed: 19592714google scholar: lookup

Citations

This article has been cited 25 times.
Subscribe to our newsletter
Join 99,727 horse owners like you who receive our email updates on horse health and nutrition.