Virology/Gag Proteins

The Gag polyprotein is a protein constructed from the nucleotide sequence of a retrovirus’s RNA sequence. These Gag polyproteins are used in the viral replication cycle of a retrovirus. The assembly and release of retrovirus particles from the cell membrane is directed by the Gag polyprotein.2 Utilizing methods of protein sequencing, scientists can now start to understand how these proteins can interact with the host cells and prevent infection. Currently, no approach has been exploited in determining antiviral therapy utilizing Gag proteins due to the lack of knowledge concerning the structures and interactions responsible for assembly. (1)

The Rous sarcoma virus (RSV) mediates its traffic via the Gag protein through the nucleus. We previously reported that nuclear localization of RSV Gag is linked to efficient packaging of viral genomic RNA; however the intranuclear activities of RSV Gag (proteins) are not well understood.(3)

The sequence of the Gag protein depends on Gag-nucleic acid interactions. The nucleic acids as short as 20-40 nucleotides can support assembly in vitro. (1)

Retroviruses are divided into two subfamilies; Orthoretrovirinae and Spumaretrovirinae. (2) The Gag proteins that are expressed within these families share no conservation of sequences; however, the homology of the proteins share strikingly similar structural resemblances.(1)

Since the Gag protein is the fundamental building block of the retrovirus particles, one expression of the gene into this protein is sufficient enough for replication of virus-like particles.1 The Gag protein itself has multiple domains within the complex. This multi-domain of the Gag protein participates in interactions with lipids in the plasma membrane, RNAs, and other Gag molecules.(1)

Gag proteins undergo conformational changes during virus particle assembly. In a Gag protein there is an N-terminal matrix domain (MA) and a C-terminal nucleocapsid domain (NC). Although both domains are positively charged and have affinities for negatively charged ions, the matrix domain has a high affinity for lipids due to the presence of phosphatidyl inositol (4,5) bisphosphate and the nucleocapsid domain has a high affinity for nucleic acids. This affinity allows for the Gag protein to become rod-like upon entering the plasma membrane of the nucleous that contains nucleic acids.(1)

The Gag protein's nucleocapsid domain has a higher affinity for a viral RNA sequence located within a non-viral RNA stretch. The viral RNA sequence is classified as "Psi". In the absence of Psi containing RNA, assembly into normal-looking virus like particles has been observed, thus indicating non-selectivity. A striking exception to the general rule is that although the nucleocapsid domain of Gag is positively charged and is essential for nucleic acid interactions in most retroviruses, it is neutral in the delta-retroviruses.(1)

As stated before, Gag proteins also aid in the packaging of vRNA. All retroviral vRNAs are packaged into virus particles in dimeric form. In murine leukemia virus (MLV), the contacts between two monomers in the dimer include the extended base-paired stretches PAL1 and PAL2, palendromic sites. (1)

It is important to understand the sequencing and actions of these Gag polyproteins. If scientists can target Gag protein synthesis then the construction of the Gag protein, packaging of the RNA for infection, and primerization of the viral DNA synthesis can be stopped.(1)

1. Diverse interactions of retroviral Gag proteins with RNAs. (2012). Alan Rein, Siddhartha A.K. Datta, Christpher P. Jones and Karin Musier-Forsyth Retrieved November 20, 2012 from http://www.ncbi.nlm.nih.gov/pubmed/21550256

2. Retroviruses. (2009). National Center of Biotechnological Information Retrieved November 20, 2012 from http://www.ncbi.nlm.nih.gov/retroviruses/

3. NC-mediated nucleolar localization of retroviral gag proteins. (2012). Lochmann TL, Bann DV, Ryan EP, Beyer AR, Mao A, Cochrane A, Parent LJ. Retrieved November 20, 2012 from http://www.ncbi.nlm.nih.gov/pubmed/23036987