VPg

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VPg (viral protein genome-linked) is a protein that is covalently attached to the 5′ end of positive strand viral RNA and acts as a primer during RNA synthesis in a variety of virus families including Picornaviridae and Caliciviridae. The primer activity of VPg occurs when the protein becomes uridylylated, providing a free hydroxyl that can be extended by the virally encoded RNA-dependent RNA polymerase. Aside from functioning as a primer, VPg also has a role in translation initiation by acting like a 5' mRNA cap.

VPg was first described in initial investigations of poliovirus RNA as a protein covalently attached to the 5' end of the genome.[1][2] and later seen in caliciviruses.[3]

Attachment during RNA synthesis

VPg must undergo post-translational uridylylation before it can act as a primer for replication. 3Dpol (the RdRp) is able to synthesize Vpg-pUpU-OH by using a polyA sequence within a stem-loop structure (cis-acting replication element) of 2C-ATPase as a template.[4][5][6] Furthermore, a 5' terminal cloverleaf is required in cis to form the 3Dpol preinitiation RNA replication complex involved in uridylylating VPg.[7]

3CDpro (a protease) cleaves VPg from membrane-bound 3AB.

Function as a 5' cap

Studies that used proteinase K to cleave VPg from the viral genome discovered that calicivirus vesicular exanthema virus lacking VPg is no longer infectious[8] whereas poliovirus retains infectivity even with the absence of VPg.[9] Because VPg sits at the 5' end of the genome, similar to eukaryotic 5' mRNA caps, several experiments were performed to explore its function in translation. Interestingly, poliovirus utilizes an internal ribosome entry site (IRES) instead of a cap for translation initiation, abrogating the requirement of VPg in initial infection[10] whereas studies with feline calicivirus confirmed that the VPg protein interacts directly with the cap-binding protein of the ribosome, eIF4E, and that this interaction is essential for viral translation.[11]

Sources

Principles of Virology by S.J. Flint, L.W. Enquist, V.R. Racaniello, A.M. Skalka (ISBN 1-55581-259-7)

  1. ↑ Flanegan JB, Petterson RF, Ambros V, Hewlett MJ, Baltimore D. Covalent linkage of a protein to a defined nucleotide sequence at the 5′-terminus of virion and replicative intermediate rnas of poliovirus. Proc Natl Acad Sci U SA. 1977;74:961–965.
  2. ↑ Lee YF, Nomoto A, Detjen BM, Wimmer E. The genome-linked protein of picornaviruses i. A protein covalently linked to poliovirus genome rna. Proc Natl Acad Sci U S A. 1977;74:59–63.
  3. ↑ Schaffer FL, Ehresmann DW, Fretz MK, Soergel MI. A protein, vpg, covalently linked to 36s calicivirus rna. J Gen Virol. 1980;47(1):215–220.
  4. ↑ Goodfellow I, Chaudhry Y, Richardson A, Meredith J, Almond J W, Barclay W, Evans D J. Identification of a cis-acting replication element within the poliovirus coding region. J Virol. 2000;74:4590–4600.
  5. ↑ Paul A V, Rieder E, Kim D W, van Boom J H, Wimmer E. Identification of an RNA hairpin in poliovirus RNA that serves as the primary template in the in vitro uridylylation of VPg. J Virol. 2000;74:10359–10370.
  6. ↑ Rieder E, Paul A V, Kim D W, van Boom J H, Wimmer E. Genetic and biochemical studies of poliovirus cis-acting replication element cre in relation to VPg uridylylation. J Virol. 2000;74:10371–10380.
  7. ↑ Lyons T, Murray KE, Roberts AW, Barton DJ. Poliovirus 5′-terminal cloverleaf RNA is required in cis for VPg uridylylation and the initiation of negative-strand RNA synthesis. J Virol. 2001;75(22):10696–708.
  8. ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus rna. J Gen Virol. 1978;41(2):443–446.
  9. ↑ Van der Werf S, Bradley J, Wimmer E, Studier FW, Dunn JJ. Synthesis of infectious poliovirus rna by purified t7 rna polymerase. Proc Natl Acad Sci. 1986;83:2330–2334.
  10. ↑ Fitzgerald KD, Semler BL. Bridging ires elements in mrnas to the eukaryotic translation apparatus. Biochim Biophys Acta. 2009;1789(9-10):518–528.
  11. ↑ Goodfellow I, Chaudhry Y, Gioldasi I, Gerondopoulos A, Natoni A, Labrie L, Laliberte JF, Roberts L. Calicivirus translation initiation requires an interaction between vpg and eif 4 e. EMBO Rep. 2005;6(10):968–972.
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