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VP6  -  major inner capsid protein

Rotavirus C

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Disease relevance of VP6

  • The VP6 gene of human group C rotavirus was cloned and sequenced [1].
  • Self-assembled virus like particles (VLPs) composed by VP2, VP6 and VP7 rotavirus proteins (VLPs 2/6/7) were produced in 5l scale using the insect cells/baculovirus expression system [2].
  • The difference map between the two structures reveals a novel large globular domain of VP4 buried within the virion that interacts extensively with the intermediate shell protein, VP6 [3].
  • However, IgA mAb's directed against the intermediate capsid protein VP6, which do not neutralize the virus, have also been shown to protect mice from rotavirus infection and clear chronic infection in SCID mice [4].
  • Intranasal immunization of mice with a chimeric VP6 protein and the mucosal adjuvant Escherichia coli heat labile toxin LT(R192G) induces nearly complete protection against murine rotavirus (strain EDIM [epizootic diarrhea of infant mice virus]) shedding for at least 1 year [5].

High impact information on VP6


Chemical compound and disease context of VP6

  • Phylogenetic analysis of VP4, VP6, VP7, and NSP4 genes of CMH222 revealed a common evolutionary lineage with simian and caprine rotavirus strains [10].
  • The inner protein shell of human rotavirus consists of a single polypeptide called VP6 which was removed from the single-shelled virus by treatment with CaCl2, leaving the viral core [11].
  • The genes encoding the glycoprotein VP7, the VP8* trypsin-cleavage product of the protein VP4, a fragment of the protein VP6 associated with subgroup (SG) specificity, and the enterotoxin NSP4 of rotavirus strains identified in diarrheic fecal samples of rabbits in Italy were sequenced [12].
  • The baculovirus-expressed gene 5 polypeptide is 44 kDa, the same as for the major inner capsid protein present on EDTA-treated ADRV virions and in vitro-expressed VP6 protein [13].
  • Therefore, parenteral immunization with VP6 alone elicited large anti-rotavirus IgG responses but did not elicit protection against murine rotavirus infection in this model [14].

Biological context of VP6

  • The complete human VP6 sequence contained an open reading frame of 1185 nucleotides (395 amino acids; deduced Mr 44,669 Da) [1].
  • Throughout the study period, G3 was the most frequent G serotype in both adults and children (detection rates 86.2 and 87.8%, respectively), and was mostly associated with VP4 genotype P[8], VP 6 genotype II (subgroup II), and NSP4 genotype B [15].
  • The inferred amino acid sequence reveals VP6 to be a polypeptide of 397 amino acids in which more than 90% of the amino acid sequence is conserved between the two viruses [16].
  • Phenotypic segregation analysis identified RRV genome segment 6 (VP6) as a secondary determinant of the spread of virus to the MLN (P = 0.02) in reassortant viruses containing segment 7 from the spread-incompetent parent [17].
  • These data suggest that in the orally infected neonatal mouse, the extraintestinal spread of rotavirus occurs via a lymphatic pathway, and the spread phenotype is primarily determined by NSP3 and can be modified by VP6 [17].

Anatomical context of VP6


Associations of VP6 with chemical compounds

  • Analyses of VP6 and NSP4 sequences showed a close relationship with simian VP6 SG I and caprine NSP4 genotype C, respectively [10].
  • These observations showed that under conditions in which histidine residues are not charged, the properties of VP6 depended on the presence of the centrally coordinated zinc atom in the trimer [22].
  • However, a single-amino-acid change from proline to glutamine at position 309 slightly affected the electrophoretic mobility of the VP6 monomer of the R6 mutant and reduced the stability of VP6 trimers on gels and at low pH values compared with the normal gene product [23].
  • Indeed, wild-type VP6 depleted of the zinc ion by a high concentration (100 mM) of a metal-chelating agent behaved like the H153 mutant proteins [22].
  • Both proteins behaved like authentic VP6 protein with EDTA and heat treatment [24].

Physical interactions of VP6

  • The ability of VP6 to interact with VP2 was examined by several assays, including electron microscopy, coimmunoprecipitation, purification of VLP2/6, and monitoring of the transcriptase activity of reconstituted DLP [25].
  • The production of VP2/4/6 particles indicated that VP4 interacts with VP6 [26].
  • Deletion analysis of VP7 indicated that truncations of either the mature amino or carboxyl terminus disrupted the proper folding of the protein and were not able to coimmunoprecipitate VP6 [27].

Regulatory relationships of VP6

  • To locate the amino terminus of VP2 within the core, we have used electron cryomicroscopy and image reconstruction to determine the three-dimensional structures of recombinant virus-like particles that contain either full-length or amino-terminal-deleted forms of VP2 coexpressed with the intermediate capsid protein VP6 [28].

Other interactions of VP6

  • The presence of VP6 with VPdelta2 did not result in encapsidation of VP1 and VP3 [29].
  • We measured the levels of gene 5 and gene 6 mRNA and showed that they were not significantly different, and protein analysis indicated no difference in stability of NSP1 compared with VP6 [30].

Analytical, diagnostic and therapeutic context of VP6

  • Molecular cloning, sequence analysis and coding assignment of the major inner capsid protein gene of human group C rotavirus [1].
  • In both reconstructions, the molecular envelope of VP6 fits the atomic model determined by X-ray crystallography remarkably well [31].
  • A reverse transcription-PCR (RT-PCR) was established to amplify a 379-bp cDNA fragment (nucleotides 747 to 1126, coding for amino acids 241 to 367) of the VP6 gene of group A rotaviruses associated with subgroup (SG) specificity [32].
  • Analysis of the pseudoatomic model of the VP6 layer, obtained by placing the atomic structure of VP6 into electron microscopy reconstructions of the DLP, has identified the regions of the protein involved in interactions with the internal layer [25].
  • The X-ray structures of VP6 and a generic Fab fragment were then docked into the cryo-electron microscopy density maps, which allowed us to propose at "pseudo-atomic" resolution the locations of the amino acid residues defining the subgroup-specific epitopes [33].


  1. Molecular cloning, sequence analysis and coding assignment of the major inner capsid protein gene of human group C rotavirus. Cooke, S.J., Lambden, P.R., Caul, E.O., Clarke, I.N. Virology (1991) [Pubmed]
  2. Downstream processing of triple layered rotavirus like particles. Peixoto, C., Sousa, M.F., Silva, A.C., Carrondo, M.J., Alves, P.M. J. Biotechnol. (2007) [Pubmed]
  3. Three-dimensional visualization of the rotavirus hemagglutinin structure. Shaw, A.L., Rothnagel, R., Chen, D., Ramig, R.F., Chiu, W., Prasad, B.V. Cell (1993) [Pubmed]
  4. Inhibition of rotavirus replication by a non-neutralizing, rotavirus VP6-specific IgA mAb. Feng, N., Lawton, J.A., Gilbert, J., Kuklin, N., Vo, P., Prasad, B.V., Greenberg, H.B. J. Clin. Invest. (2002) [Pubmed]
  5. CD4 T cells are the only lymphocytes needed to protect mice against rotavirus shedding after intranasal immunization with a chimeric VP6 protein and the adjuvant LT(R192G). McNeal, M.M., VanCott, J.L., Choi, A.H., Basu, M., Flint, J.A., Stone, S.C., Clements, J.D., Ward, R.L. J. Virol. (2002) [Pubmed]
  6. Protective effect of rotavirus VP6-specific IgA monoclonal antibodies that lack neutralizing activity. Burns, J.W., Siadat-Pajouh, M., Krishnaney, A.A., Greenberg, H.B. Science (1996) [Pubmed]
  7. Atomic structure of the major capsid protein of rotavirus: implications for the architecture of the virion. Mathieu, M., Petitpas, I., Navaza, J., Lepault, J., Kohli, E., Pothier, P., Prasad, B.V., Cohen, J., Rey, F.A. EMBO J. (2001) [Pubmed]
  8. Individual rotavirus-like particles containing 120 molecules of fluorescent protein are visible in living cells. Charpilienne, A., Nejmeddine, M., Berois, M., Parez, N., Neumann, E., Hewat, E., Trugnan, G., Cohen, J. J. Biol. Chem. (2001) [Pubmed]
  9. Nucleotide sequence of group antigen (VP6) of the UK tissue culture adapted strain of bovine rotavirus. Tarlow, O., McCrae, M.A. Nucleic Acids Res. (1990) [Pubmed]
  10. Molecular characterization of a rare G3P[3] human rotavirus reassortant strain reveals evidence for multiple human-animal interspecies transmissions. Khamrin, P., Maneekarn, N., Peerakome, S., Yagyu, F., Okitsu, S., Ushijima, H. J. Med. Virol. (2006) [Pubmed]
  11. Role of the inner protein capsid on in vitro human rotavirus transcription. Sandino, A.M., Jashes, M., Faúndez, G., Spencer, E. J. Virol. (1986) [Pubmed]
  12. Molecular characterization of the VP4, VP6, VP7, and NSP4 genes of lapine rotaviruses identified in italy: emergence of a novel VP4 genotype. Martella, V., Ciarlet, M., Camarda, A., Pratelli, A., Tempesta, M., Greco, G., Cavalli, A., Elia, G., Decaro, N., Terio, V., Bozzo, G., Camero, M., Buonavoglia, C. Virology (2003) [Pubmed]
  13. Baculovirus expression of the ADRV gene 5 encoded protein produces an oligomerized, antigenic, and immunogenic VP6 protein. Mackow, E.R., Fay, M.E., Werner-Eckert, R., Hung, T., Wang, Z.J., Chen, G. Virology (1993) [Pubmed]
  14. Particle bombardment-mediated DNA vaccination with rotavirus VP6 induces high levels of serum rotavirus IgG but fails to protect mice against challenge. Choi, A.H., Knowlton, D.R., McNeal, M.M., Ward, R.L. Virology (1997) [Pubmed]
  15. Molecular epidemiologic analysis of group A rotaviruses in adults and children with diarrhea in Wuhan city, China, 2000-2006. Wang, Y.H., Kobayashi, N., Zhou, D.J., Yang, Z.Q., Zhou, X., Peng, J.S., Zhu, Z.R., Zhao, D.F., Liu, M.Q., Gong, J. Arch. Virol. (2007) [Pubmed]
  16. Comparative sequence analysis of rotavirus genomic segment 6--the gene specifying viral subgroups 1 and 2. Both, G.W., Siegman, L.J., Bellamy, A.R., Ikegami, N., Shatkin, A.J., Furuichi, Y. J. Virol. (1984) [Pubmed]
  17. A lymphatic mechanism of rotavirus extraintestinal spread in the neonatal mouse. Mossel, E.C., Ramig, R.F. J. Virol. (2003) [Pubmed]
  18. Association of Gamma Interferon and Interleukin-17 Production in Intestinal CD4+ T Cells with Protection against Rotavirus Shedding in Mice Intranasally Immunized with VP6 and the Adjuvant LT(R192G). Smiley, K.L., McNeal, M.M., Basu, M., Choi, A.H., Clements, J.D., Ward, R.L. J. Virol. (2007) [Pubmed]
  19. Engineering of immunogenic peptides by co-linear synthesis of determinants recognized by B and T cells. Borras-Cuesta, F., Petit-Camurdan, A., Fedon, Y. Eur. J. Immunol. (1987) [Pubmed]
  20. Identification of an HLA-A*0201-restricted cytotoxic T-lymphocyte epitope in rotavirus VP6 protein. Wei, J., Li, J.T., Zhang, X.P., Tang, Y., Wang, J.X., Zhang, B., Wu, Y.Z. J. Gen. Virol. (2006) [Pubmed]
  21. Rotavirus VP6 modified for expression on the plasma membrane forms arrays and exhibits enhanced immunogenicity. Reddy, D.A., Bergmann, C.C., Meyer, J.C., Berriman, J., Both, G.W., Coupar, B.E., Boyle, D.B., Andrew, M.E., Bellamy, A.R. Virology (1992) [Pubmed]
  22. A zinc ion controls assembly and stability of the major capsid protein of rotavirus. Erk, I., Huet, J.C., Duarte, M., Duquerroy, S., Rey, F., Cohen, J., Lepault, J. J. Virol. (2003) [Pubmed]
  23. Rearrangement of the VP6 gene of a group A rotavirus in combination with a point mutation affecting trimer stability. Shen, S., Burke, B., Desselberger, U. J. Virol. (1994) [Pubmed]
  24. Rotavirus 993/83, isolated from calf faeces, closely resembles an avian rotavirus. Brüssow, H., Nakagomi, O., Minamoto, N., Eichhorn, W. J. Gen. Virol. (1992) [Pubmed]
  25. Identification of rotavirus VP6 residues located at the interface with VP2 that are essential for capsid assembly and transcriptase activity. Charpilienne, A., Lepault, J., Rey, F., Cohen, J. J. Virol. (2002) [Pubmed]
  26. Characterization of virus-like particles produced by the expression of rotavirus capsid proteins in insect cells. Crawford, S.E., Labbé, M., Cohen, J., Burroughs, M.H., Zhou, Y.J., Estes, M.K. J. Virol. (1994) [Pubmed]
  27. Rotavirus assembly - interaction of surface protein VP7 with middle layer protein VP6. Gilber, J.M., Feng, N., Patton, J.T., Greenberg, H.B. Arch. Virol. (2001) [Pubmed]
  28. Three-dimensional structural analysis of recombinant rotavirus-like particles with intact and amino-terminal-deleted VP2: implications for the architecture of the VP2 capsid layer. Lawton, J.A., Zeng, C.Q., Mukherjee, S.K., Cohen, J., Estes, M.K., Prasad, B.V. J. Virol. (1997) [Pubmed]
  29. The N terminus of rotavirus VP2 is necessary for encapsidation of VP1 and VP3. Zeng, C.Q., Estes, M.K., Charpilienne, A., Cohen, J. J. Virol. (1998) [Pubmed]
  30. Translational regulation of rotavirus gene expression. Mitzel, D.N., Weisend, C.M., White, M.W., Hardy, M.E. J. Gen. Virol. (2003) [Pubmed]
  31. Structural polymorphism of the major capsid protein of rotavirus. Lepault, J., Petitpas, I., Erk, I., Navaza, J., Bigot, D., Dona, M., Vachette, P., Cohen, J., Rey, F.A. EMBO J. (2001) [Pubmed]
  32. Molecular characterization of VP6 genes of human rotavirus isolates: correlation of genogroups with subgroups and evidence of independent segregation. Iturriza Gómara, M., Wong, C., Blome, S., Desselberger, U., Gray, J. J. Virol. (2002) [Pubmed]
  33. Structural determinants of rotavirus subgroup specificity mapped by cryo-electron microscopy. Greig, S.L., Berriman, J.A., O'Brien, J.A., Taylor, J.A., Bellamy, A.R., Yeager, M.J., Mitra, A.K. J. Mol. Biol. (2006) [Pubmed]
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