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Structural roles of PCV2 capsid protein N-terminus in PCV2 particle assembly and identification of PCV2 type-specific neutralizing epitope.

Mo X, Li X, Yin B, Deng J, Tian K, Yuan A
PLoS Pathog 15 e1007562 (2019)
Cited: 20 times
EuropePMC logo PMID: 30822338

Abstract

Postweaning multisystemic wasting disease (PMWS) in piglets caused by porcine circovirus type 2 (PCV2) is one of the major threats to most pig farms worldwide. Among all the PCV types, PCV2 is the dominant genotype causing PMWS and associated diseases. Considerable efforts were made to study the virus-like-particle (VLP) assembly and the specific PCV2-associated epitope(s) in order to establish the solid foundation for engineered PCV2 vaccine development. Although the N-terminal fragment including Nuclear Localization Signal (NLS) sequence seems important for recombinant PCV2 capsid protein expression and VLP assembly, the detailed structural and functional information regarding this important fragment are largely unknown. In this study, we report crystal structure of PCV2 VLP assembled from N-terminal NLS truncated PCV2 capsid protein at 2.8 Å resolution and cryo-EM structure of PCV2 VLP assembled from full-length PCV2 capsid protein at 4.1Å resolution. Our in vitro PCV2 VLP assembly results show that NLS-truncated PCV2 capsid protein only forms instable VLPs which were easily disassembled in solution, whereas full-length PCV2 capsid protein forms stable VLPs due to interaction between 15PRSHLGQILRRRP27 (α-helix) and 33RHRYRWRRKN42 (NLS-B) in a repeated manner. In addition, our results also showed that N-terminal truncation of PCV2 capsid protein up to 27 residues still forms PCV2 particles in solution with similar size and immunogenicity, while N-terminal truncation of PCV2 capsid protein with more than 30 residues is not able to form stable PCV2 particles in solution, demonstrating the importance of interaction between the α-helix at N-terminal and NLS-B in PCV2 VLP formation. Moreover, we also report the cryo-EM structure of PCV2 VLP in complex with 3H11-Fab, a PCV2 type-specific neutralizing antibody, at 15 Å resolution. MAb-3H11 specifically recognizes one exposed epitope located on the VLP surface EF-loop (residues 128-143), which is further confirmed by PCV1-PCV2 epitope swapping assay. Hence, our results have revealed the structural roles of N-terminal fragment of PCV2 capsid protein in PCV2 particle assembly and pinpointed one PCV2 type-specific neutralizing epitope for the first time, which could provide clear clue for next generation PCV2 vaccine and diagnostic kits development.

Articles - 5zbo mentioned but not cited (1)

  1. Structural roles of PCV2 capsid protein N-terminus in PCV2 particle assembly and identification of PCV2 type-specific neutralizing epitope. Mo X, Li X, Yin B, Deng J, Tian K, Yuan A. PLoS Pathog 15 e1007562 (2019)


Reviews citing this publication (1)

  1. Advances in Crosstalk between Porcine Circoviruses and Host. Niu G, Chen S, Li X, Zhang L, Ren L. Viruses 14 1419 (2022)

Articles citing this publication (18)

  1. Macrophage Polarization Modulated by Porcine Circovirus Type 2 Facilitates Bacterial Coinfection. Zhang W, Fu Z, Yin H, Han Q, Fan W, Wang F, Shang Y. Front Immunol 12 688294 (2021)
  2. Structural characterization of the PCV2d virus-like particle at 3.3 Å resolution reveals differences to PCV2a and PCV2b capsids, a tetranucleotide, and an N-terminus near the icosahedral 3-fold axes. Khayat R, Wen K, Alimova A, Gavrilov B, Katz A, Galarza JM, Gottlieb P. Virology 537 186-197 (2019)
  3. Structural insight into the type-specific epitope of porcine circovirus type 3. Bi M, Li X, Zhai W, Yin B, Tian K, Mo X. Biosci Rep 40 BSR20201109 (2020)
  4. C1QBP inhibits proliferation of porcine circovirus type 2 by restricting nuclear import of the capsid protein. Ma X, Lv C, Wang Q, Li C, Wang P, Luo C, Wu Y, Wei T, Liu S, Adam FEA, Yang Z, Wang X. Arch Virol 166 767-778 (2021)
  5. Molecular genotypic analysis of porcine circovirus type 2 reveals the predominance of PCV2d in Vietnam (2018-2020) and the association between PCV2h, the recombinant forms, and Vietnamese vaccines. Doan HTT, Do RT, Thao PTP, Le XTK, Nguyen KT, Hien NTT, Duc LM, Pham LTK, Le TH. Arch Virol 167 2011-2026 (2022)
  6. Selection and Characterization of a Single-Chain Variable Fragment against Porcine Circovirus Type 2 Capsid and Impedimetric Immunosensor Development. Klangprapan S, Weng CC, Huang WT, Li YK, Choowongkomon K. ACS Omega 6 24233-24243 (2021)
  7. Combining Phage Display Technology with In Silico-Designed Epitope Vaccine to Elicit Robust Antibody Responses against Emerging Pathogen Tilapia Lake Virus. Gong YM, Wei XF, Zheng YY, Li Y, Yu Q, Li PF, Zhu B. J Virol 97 e0005023 (2023)
  8. A Novel Virus-Like Agent Originated From Genome Rearrangement of Porcine Circovirus Type 2 (PCV2) Enhances PCV2 Replication and Regulates Intracellular Redox Status In Vitro. Feng H, Fu J, Zhang B, Xue T, Liu C. Front Cell Infect Microbiol 12 855920 (2022)
  9. Evaluation of a Virus-like Nanoparticle Porcine Circovirus Type-2 (PCV2) Capsid Protein Fused with the Pig Immunoglobulin Fc Fragment as a Novel Vaccine Candidate against PCV2 in Mice. Luo Q, Ahmed W, Dai Y, Mohsin A, Hang H, Zhuang Y, Guo M. Vaccines (Basel) 9 1128 (2021)
  10. Immunogenicity Analysis of PCV3 Recombinant Capsid Protein Virus-like Particles and Their Application in Antibodies Detection. Cao X, Huang M, Wang Y, Chen Y, Yang H, Quan F. Int J Mol Sci 24 10377 (2023)
  11. N-Terminus-Mediated Solution Structure of Dimerization Domain of PRC1. Tan F, Xu J. Curr Issues Mol Biol 44 1626-1645 (2022)
  12. Validation of the solution structure of dimerization domain of PRC1. Tan F, Xu J. PLoS One 17 e0270572 (2022)
  13. miR-214-5p/C1QTNF1 axis enhances PCV2 replication through promoting autophagy by targeting AKT/mTOR signaling pathway. Cao Y, Jing P, Yu L, Wu Z, Gao S, Bao W. Virus Res 323 198990 (2023)
  14. Constant pH molecular dynamics of porcine circovirus 2 capsid protein reveals a mechanism for capsid assembly. Tarasova E, Okimoto N, Feng S, Nerukh D, Khayat R, Taiji M. Phys Chem Chem Phys 23 24617-24626 (2021)
  15. Evaluation of Methylotrophic Yeast Ogataea thermomethanolica TBRC 656 as a Heterologous Host for Production of an Animal Vaccine Candidate. Liwnaree B, Muensaen K, Narkpuk J, Promdonkoy P, Kocharin K, Peswani AR, Robinson C, Mikaliunaite L, Roongsawang N, Tanapongpipat S, Jaru-Ampornpan P. Mol Biotechnol 64 1288-1302 (2022)
  16. Immunogenicity and Immunoprotection of PCV2 Virus-like Particles Incorporating Dominant T and B Cell Antigenic Epitopes Paired with CD154 Molecules in Piglets and Mice. Wu K, Hu W, Zhou B, Li B, Li X, Yan Q, Chen W, Li Y, Ding H, Zhao M, Fan S, Yi L, Chen J. Int J Mol Sci 23 14126 (2022)
  17. The Nuclear Localization Signal of Porcine Circovirus Type 4 Affects the Subcellular Localization of the Virus Capsid and the Production of Virus-like Particles. Zheng J, Li N, Li X, Han Y, Lv X, Zhang H, Ren L. Int J Mol Sci 25 2459 (2024)
  18. The ultrasonically treated nanoliposomes containing PCV2 DNA vaccine expressing gC1qR binding site mutant Cap is efficient in mice. Du Q, Shi T, Wang H, Zhu C, Yang N, Tong D, Huang Y. Front Microbiol 13 1077026 (2022)


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