2012
DOI: 10.1016/j.jmb.2012.01.033 View full text |Buy / Rent full text
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Abstract: Assembly of Human Immunodeficiency Virus Type-1 (HIV-1) particles is initiated in the cytoplasm by the formation of a ribonucleoprotein complex comprising the dimeric RNA genome and a small number of viral Gag polyproteins. Genomes are recognized by the nucleocapsid (NC) domains of Gag, which interact with packaging elements believed to be located primarily within the 5´-leader of the viral RNA. Recent studies revealed that the native 5´-leader exists as an equilibrium of two conformers, one in which dimer-pro… Show more

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“…Because the 5′-Cap and 5′-G moieties have similar influences on the monomer-dimer equilibrium, it seems plausible that the overhanging 5′ Cap of the Cap 2G transcript also stabilizes the monomer by interacting with C58 and disrupting the PolyA helix. This model is compatible with studies showing that deletion of the TAR or PolyA hairpins does not significantly affect 5′-L dimerization or vector packaging (39), whereas mutations that open the lower helix of TAR inhibit both dimerization and packaging (44,45).…”
Section: Discussionsupporting
“…Similarly, mutations that prevent dimerization of the recombinant 5′-L RNA of the Moloney murine leukemia virus (MLV) block packaging (40), suggesting that dimerization-dependent control mechanisms are conserved among evolutionarily distant retroviruses (40,41). MLV-derived vectors harboring monomer-stabilizing mutations remain unpackaged in the absence of competing wild-type leader RNAs (40), whereas mutations that shift the equilibrium of the HIV-1 5′-L in favor of the monomer but do not prevent dimerization do not prevent the HIV-1 RNA from functioning as both genome and mRNA in the absence of wild-type competition (26,39,42). These and other observations support a mechanism in which a single viral transcript equilibrates between structures associated with alternate replication functions (9,12,16,26,29).…”
Section: Discussionmentioning
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“…In MLV, dimerization of the gRNA exposes high-affinity binding sites for the NC domain of Gag (D'Souza and Summers 2004;Gherghe et al 2010;Miyazaki et al 2010), suggesting that packaging and Gag binding to ψ are coordinated with dimerization. In HIV-1, a 159-nt "core encapsidation signal" was recently described that binds NC with similar affinity as the full-length 5 ′ leader sequence (Heng et al 2012). However, there may be important differences in the mechanisms by which the discrete NC domain and the full-length Gag protein bind to gRNA with high affinity.…”
Section: Thementioning
“…Additional mutational studies helped define a minimal core encapsidation signal (Ψ CES ) within the leader that retains the key structural features of the dimer, as well as elements needed to direct packaging (Fig. 1B) (20). Using a segmental labeling strategy, the authors went on to solve a high-resolution structure of the 155-nt Ψ CES , which is the largest RNA structure determined by NMR to date (21).…”
mentioning