The matrix (MA) domain of the HIV-1 Gag polyprotein is responsible for targeting the Gag-genome complex to the plasma membrane for virion assembly. This targeting is mediated through specific interactions between the highly basic patch (HBR) on MA and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] on the plasma membrane. The myristoyl group on MA adopts an exposed conformation to anchor Gag to the membrane after initial HBR interactions. Mutations of basic residues in the HBR can lead to retargeting of Gag from the plasma membrane to multivesicular bodies (MVBs) and a decrease in MA’s specificity for PI(4,5)P2-containing membranes. In addition to PI(4,5)P2, MA specifically binds to some cellular tRNAs, including the tRNALys3 which is packaged into virions and serves as the primer for reverse transcription. Isothermal titration calorimetry (ITC) was used to investigate MA and tRNALys3 interactions, and to determine the role basic patch residues play in MA’s ability to bind tRNALys3. Mutations that cause retargeting of Gag to MVBs also resulted in decreased affinity of MA for tRNALys3, suggesting the residues may play a role in both processes. ITC experiments with myristoyl exposure-deficient mutants indicated a potential role for the myristoyl group in regulating tRNA binding, as increased myristoyl exposure weakened tRNA-MA interactions.

Role of HIV-1's highly basic patch and myristoyl group on matrix-tRNA interactions

254th National Meeting (2017)

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