Differences and commonalities in plasma membrane recruitment of the two morphogenetically distinct retroviruses HIV-1 and MMTV

Abstract

<jats:p>Retroviral Gag polyproteins are targeted to the inner leaflet of the plasma membrane through their N-terminal matrix (MA) domain. Because retroviruses of different morphogenetic types assemble their immature particles in distinct regions of the host cell, the mechanism of MA-mediated plasma membrane targeting differs among distinct retroviral morphogenetic types. Here, we focused on possible mechanistic differences of the MA-mediated plasma membrane targeting of the B-type mouse mammary tumor virus (MMTV) and C-type HIV-1, which assemble in the cytoplasm and at the plasma membrane, respectively. Molecular dynamics simulations, together with surface mapping, indicated that, similarly to HIV-1, MMTV uses a myristic switch to anchor the MA to the membrane and electrostatically interacts with phosphatidylinositol 4,5-bisphosphate to stabilize MA orientation. We observed that the affinity of MMTV MA to the membrane is lower than that of HIV-1 MA, possibly related to their different topologies and the number of basic residues in the highly basic MA region. The latter probably reflects the requirement of C-type retroviruses for tighter membrane binding, essential for assembly, unlike for D/B-type retroviruses, which assemble in the cytoplasm. A comparison of the membrane topology of the HIV-1 MA, using the surface-mapping method and molecular dynamics simulations, revealed that the residues at the HIV-1 MA C terminus help stabilize protein–protein interactions within the HIV-1 MA lattice at the plasma membrane. In summary, HIV-1 and MMTV share common features such as membrane binding of the MA via hydrophobic interactions and exhibit several differences, including lower membrane affinity of MMTV MA.</jats:p>

Precursors of Viral Proteases as Distinct Drug Targets

“…Gag [ 131 , 132 ] and Gag-Pol polyproteins are recruited to the cell membrane, which is the site of viral assembly [ 133 ]. In HIV, the N-terminal myristoyl moiety of Gag anchors viral proteins to the cell membrane.…”

Rendezvous at Plasma Membrane: Cellular Lipids and tRNA Set up Sites of HIV-1 Particle Assembly and Incorporation of Host Transmembrane Proteins

“…Therefore, both negative charge density of the inositol headgroup and distribution of the phosphate residues on the inositol ring are likely determinants for the optimal interaction between MA and PI(4,5)P2. Recent genetic and structural studies collectively suggest that HBR residues Lys 29 and Lys 31, especially Lys 31, play key roles in the interaction with the PI(4,5)P2 headgroup, although other basic residues may also be involved [ 41 , 48 , 78 , 79 , 80 ]. In addition, as we discuss later, binding of RNA to MA-HBR residues is also likely to contribute to lipid specificity.…”