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VP4  -  outer capsid spike protein

Rotavirus C

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Disease relevance of VP4

  • In vitro, simply adding the recombinant outer capsid proteins VP4 and VP7 to authentic double-layered rotavirus subviral particles (DLPs) in the presence of calcium and acidic pH increases infectivity by a factor of up to 10(7), yielding particles as infectious as authentic purified virions [1].
  • 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 [2].
  • The spike protein VP4 is a key component of the membrane penetration apparatus of rotavirus, a nonenveloped virus that causes childhood gastroenteritis [3].
  • DARTT was applied to rhesus rotavirus gene segment 4 cDNA in order to create a series of carboxyl-terminal truncations and new amino termini in the encoded VP4 capsid protein [4].
  • With the aid of helper virus (human RV strain KU) infection, intracellularly transcribed full-length VP4 mRNA of simian RV strain SA11 resulted in the rescue of the KU-based transfectant virus carrying the SA11 VP4 RNA segment derived from cDNA [5].

High impact information on VP4

  • Our results suggest that assembly of VP4 precedes that of VP7, the major outer shell protein, and that VP4 may play an important role in the receptor recognition and budding process through the rough endoplasmic reticulum during virus maturation [2].
  • VP4 in these viruses has been implicated in several important functions such as cell penetration, haemagglutination, neutralization and virulence [6].
  • Trypsin cleavage of VP4 produces a fragment, VP5*, with a potential membrane interaction region, and primes rotavirus for cell entry [3].
  • The rhesus rotavirus VP4 sialic acid binding domain has a galectin fold with a novel carbohydrate binding site [7].
  • In addition to the rescued transfectant virus with the authentic SA11 VP4 gene, three more infectious RV transfectants, into which silent mutation(s) were introduced to destroy both or one of the two restriction enzyme sites as gene markers in the SA11 VP4 genome, were also rescued with this method [5].

Chemical compound and disease context of VP4

  • An unusual strain of human rotavirus G3P[3] (CMH222), bearing simian-like VP7 and caprine-like VP4 genes, was isolated from a 2-year-old child patient during the epidemiological survey of rotavirus in Chiang Mai, Thailand in 2000-2001 [8].
  • Rotavirus VP4-mediated cell entry may involve the alpha2beta1 integrin, whereas VP7 appears to interact with alphaxbeta2 and alpha4beta1 integrins [9].
  • Characterization of recombinant polioviruses expressing regions of rotavirus VP4, hepatitis B surface antigen, and herpes simplex virus type 2 glycoprotein D [10].
  • Cleavage of rhesus rotavirus VP4 after arginine 247 is essential for rotavirus-like particle-induced fusion from without [11].
  • This information, together with our previous identification of an 84-kDa protein present on iodinated intact virion but not EDTA-treated ADRV, suggests that gene 4 encodes the VP4 protein equivalent present on the outer capsid of ADRV [12].

Biological context of VP4

  • Nucleotide sequence comparisons of the Bristol and Belém VP4 genes revealed 45 differences of which only 6 were predicted to give amino acid changes [13].
  • Human group C rotavirus genome segment 3 contains 2283 bp and encodes the VP4 gene with an open reading frame of 2232 nucleotides (744 amino acids) starting at nucleotide 21 and terminating at nucleotide 2251 [13].
  • 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 [14].
  • The VP4 sequence of CMH222 shared the greatest homology with those of caprine P[3] (GRV strain) at 90.6% nucleotide and 96.4% amino acid sequence identities [8].
  • Furthermore, RFLP analysis of these G1P[8] strains, clearly differentiated the viruses into two main clusters, both of them sharing the same restriction pattern for the VP4 gene, and a different one for the VP7 gene [15].

Anatomical context of VP4

  • We show that VP4 and VP7 contain tripeptide sequences previously shown to act as recognition sites for integrins in extracellular matrix proteins [9].
  • In addition, we have determined that the baculovirus-expressed VP4 protein bound to erythrocytes and functions as the RRV hemagglutinin [16].
  • Previous studies indicated that VP4 is located in the space between the periphery of the viroplasm and the outside of the endoplasmic reticulum in rotavirus-infected cells [17].
  • The present data suggest that VP4 reaches the plasma membrane through the microtubule network and that other viral proteins are dispensable for its targeting and transport [17].
  • Following immunization of mice with double-shelled virus particles and VP4-enriched fractions from CsCl gradients, a battery of anti-SA11 hybridomas was generated [18].

Associations of VP4 with chemical compounds

  • VP4 contains the alpha2beta1 integrin ligand site DGE [9].
  • The domains of VP4 defined by protease analysis contain all mapped neutralizing epitopes, sialic acid binding residues, the heptad repeat region, and the membrane permeabilization region [19].
  • Biotin labeling of the infected cell surface monolayer with a cell-impermeable reagent allowed the identification of the noncleaved form of VP4 that was associated with the glycoprotein VP7 [17].
  • It was shown that in addition to arginine residues 241 and 247, VP4 is cleaved at arginine residue 231 [20].
  • VP4 does not colocalize with the ER marker protein disulfide-isomerase even when viral particles were blocked by TM in this compartment [21].

Physical interactions of VP4

  • The parameters for efficient recoating and the characterization of recoated particles suggest a model in which, after a relatively weak interaction between oligomeric VP4 and DLPs, VP7 binds the particles and locks VP4 in place [1].
  • The production of VP2/4/6 particles indicated that VP4 interacts with VP6 [22].

Regulatory relationships of VP4


Other interactions of VP4

  • These results, combined with the in vivo properties of PP-1 in the two target species, supported the concept that species-specific VP4 and NSP4, but not NSP1, are required to induce rotavirus disease, at least in calves and pigs [25].

Analytical, diagnostic and therapeutic context of VP4

  • PCR primers designed from the 5' and 3' terminal sequences of the C/Bristol VP4 gene were used to amplify the corresponding VP4 gene of a human group C rotavirus from Belém, Brazil [13].
  • Protein sequence alignments showed that the human group C rotavirus VP4 sequences were 8 amino acids longer than the porcine VP4 sequence with an insertion of 6 amino acids, 252NSKLGD257 adjacent to the proposed proteolytic cleavage region (amino acids 231-250) [13].
  • Sequence analysis of VP4-encoding genes of the G1 strains revealed that the older strains were associated with a unique VP4 lineage, while a novel VP4 lineage emerged after 1995 [26].
  • The continuous emergence of VP7-VP4 gene combinations in human rotavirus strains should be taken into consideration when devising vaccination strategies [26].
  • G- and P-typing of the positive samples were accomplished by amplifying VP7 and VP4 genes by RT-PCR and genotyped by seminested multiplex PCR methods [27].


  1. Assembly of highly infectious rotavirus particles recoated with recombinant outer capsid proteins. Trask, S.D., Dormitzer, P.R. J. Virol. (2006) [Pubmed]
  2. 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]
  3. Alternative intermolecular contacts underlie the rotavirus VP5* two- to three-fold rearrangement. Yoder, J.D., Dormitzer, P.R. EMBO J. (2006) [Pubmed]
  4. DNA amplification-restricted transcription-translation: rapid analysis of rhesus rotavirus neutralization sites. Mackow, E.R., Yamanaka, M.Y., Dang, M.N., Greenberg, H.B. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  5. Reverse genetics system for introduction of site-specific mutations into the double-stranded RNA genome of infectious rotavirus. Komoto, S., Sasaki, J., Taniguchi, K. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  6. Localization of VP4 neutralization sites in rotavirus by three-dimensional cryo-electron microscopy. Prasad, B.V., Burns, J.W., Marietta, E., Estes, M.K., Chiu, W. Nature (1990) [Pubmed]
  7. The rhesus rotavirus VP4 sialic acid binding domain has a galectin fold with a novel carbohydrate binding site. Dormitzer, P.R., Sun, Z.Y., Wagner, G., Harrison, S.C. EMBO J. (2002) [Pubmed]
  8. 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]
  9. Rotavirus contains integrin ligand sequences and a disintegrin-like domain that are implicated in virus entry into cells. Coulson, B.S., Londrigan, S.L., Lee, D.J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  10. Characterization of recombinant polioviruses expressing regions of rotavirus VP4, hepatitis B surface antigen, and herpes simplex virus type 2 glycoprotein D. Mattion, N.M., Reilly, P.A., Camposano, E., Wu, S.L., DiMichele, S.J., Ishizaka, S.T., Fantini, S.E., Crowley, J.C., Weeks-Levy, C. J. Virol. (1995) [Pubmed]
  11. Cleavage of rhesus rotavirus VP4 after arginine 247 is essential for rotavirus-like particle-induced fusion from without. Gilbert, J.M., Greenberg, H.B. J. Virol. (1998) [Pubmed]
  12. Identification and baculovirus expression of the VP4 protein of the human group B rotavirus ADRV. Mackow, E.R., Werner-Eckert, R., Fay, M.E., Tao, H., Chen, G. J. Virol. (1993) [Pubmed]
  13. Molecular characterization of the outer capsid spike protein (VP4) gene from human group C rotavirus. Fielding, P.A., Lambden, P.R., Caul, E.O., Clarke, I.N. Virology (1994) [Pubmed]
  14. 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]
  15. Analysis of human rotavirus G1P[8] strains by RFLP reveals higher genetic drift in the VP7 than the VP4 gene during a 4-year period in Mexico. Rodr??guez-Castillo, A., Ram??rez-Gonz??lez, J.E., Padilla-Noriega, L., Barr??n, B.L. J. Virol. Methods (2006) [Pubmed]
  16. The rhesus rotavirus outer capsid protein VP4 functions as a hemagglutinin and is antigenically conserved when expressed by a baculovirus recombinant. Mackow, E.R., Barnett, J.W., Chan, H., Greenberg, H.B. J. Virol. (1989) [Pubmed]
  17. Rotavirus spike protein VP4 is present at the plasma membrane and is associated with microtubules in infected cells. Nejmeddine, M., Trugnan, G., Sapin, C., Kohli, E., Svensson, L., Lopez, S., Cohen, J. J. Virol. (2000) [Pubmed]
  18. Functional and topographical analyses of epitopes on the hemagglutinin (VP4) of the simian rotavirus SA11. Burns, J.W., Greenberg, H.B., Shaw, R.D., Estes, M.K. J. Virol. (1988) [Pubmed]
  19. Proteolysis of monomeric recombinant rotavirus VP4 yields an oligomeric VP5* core. Dormitzer, P.R., Greenberg, H.B., Harrison, S.C. J. Virol. (2001) [Pubmed]
  20. Trypsin activation pathway of rotavirus infectivity. Arias, C.F., Romero, P., Alvarez, V., López, S. J. Virol. (1996) [Pubmed]
  21. Spike protein VP4 assembly with maturing rotavirus requires a postendoplasmic reticulum event in polarized caco-2 cells. Delmas, O., Durand-Schneider, A.M., Cohen, J., Colard, O., Trugnan, G. J. Virol. (2004) [Pubmed]
  22. 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]
  23. Structures of rotavirus reassortants demonstrate correlation of altered conformation of the VP4 spike and expression of unexpected VP4-associated phenotypes. Pesavento, J.B., Billingsley, A.M., Roberts, E.J., Ramig, R.F., Prasad, B.V. J. Virol. (2003) [Pubmed]
  24. Particle-bombardment-mediated DNA vaccination with rotavirus VP4 or VP7 induces high levels of serum rotavirus IgG but fails to protect mice against challenge. Choi, A.H., Basu, M., Rae, M.N., McNeal, M.M., Ward, R.L. Virology (1998) [Pubmed]
  25. Rotavirus cross-species pathogenicity: molecular characterization of a bovine rotavirus pathogenic for pigs. El-Attar, L., Dhaliwal, W., Howard, C.R., Bridger, J.C. Virology (2001) [Pubmed]
  26. Heterogeneity and temporal dynamics of evolution of g1 human rotaviruses in a settled population. Arista, S., Giammanco, G.M., De Grazia, S., Ramirez, S., Lo Biundo, C., Colomba, C., Cascio, A., Martella, V. J. Virol. (2006) [Pubmed]
  27. Changing pattern of human group A rotaviruses: emergence of G12 as an important pathogen among children in eastern India. Samajdar, S., Varghese, V., Barman, P., Ghosh, S., Mitra, U., Dutta, P., Bhattacharya, S.K., Narasimham, M.V., Panda, P., Krishnan, T., Kobayashi, N., Naik, T.N. J. Clin. Virol. (2006) [Pubmed]
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