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NMR structure of the myristylated feline immunodeficiency virus matrix protein
Lola A Brown1, Cassiah Cox2, Janae Baptiste3
1Howard Hughes Medical Institute, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA. lola.brown@yale.edu.
Abstract:
Membrane targeting by the Gag proteins of the human immunodeficiency viruses (HIV types-1 and -2) is mediated by Gag's N-terminally myristylated matrix (MA) domain and is dependent on cellular phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. To determine if other lentiviruses employ a similar membrane targeting mechanism, we initiated studies of the feline immunodeficiency virus (FIV), a widespread feline pathogen with potential utility for development of human therapeutics. Bacterial co-translational myristylation was facilitated by mutation of two amino acids near the amino-terminus of the protein (Q5A/G6S; myrMAQ5A/G6S). These substitutions did not affect virus assembly or release from transfected cells. NMR studies revealed that the myristyl group is buried within a hydrophobic pocket in a manner that is structurally similar to that observed for the myristylated HIV-1 protein. Comparisons with a recent crystal structure of the unmyristylated FIV protein [myr(-)MA] indicate that only small changes in helix orientation are required to accommodate the sequestered myr group. Depletion of PI(4,5)P2 from the plasma membrane of FIV-infected CRFK cells inhibited production of FIV particles, indicating that, like HIV, FIV hijacks the PI(4,5)P2 cellular signaling system to direct intracellular Gag trafficking during virus assembly.
Insights
Feline immunodeficiency virus (FIV) Gag protein membrane targeting is similar to HIV, utilizing myristylation and phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. This interaction is crucial for FIV particle production and Gag trafficking during assembly.
Area of Science:
- Virology
- Molecular Biology
- Structural Biology
Background:
- Human immunodeficiency virus (HIV) membrane targeting relies on the Gag matrix (MA) domain, which is myristylated and interacts with phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2].
- Understanding lentiviral membrane targeting mechanisms is crucial for developing therapeutics and insights into viral pathogenesis.
Purpose of the Study:
- To investigate if feline immunodeficiency virus (FIV), a significant feline pathogen, employs a similar membrane targeting mechanism as HIV.
- To characterize the structural and functional role of the myristylated MA domain in FIV assembly and release.
Main Methods:
- Bacterial co-translational myristylation of FIV Gag MA domain via specific amino acid substitutions (Q5A/G6S).
- Nuclear Magnetic Resonance (NMR) and crystal structure comparisons to analyze myristyl group binding and structural changes.
- Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] depletion experiments in FIV-infected cells to assess its role in virus production.
Main Results:
- Myristylation of FIV MA domain was successfully achieved and did not impede virus assembly or release.
- NMR studies revealed structural similarities in myristyl group binding between FIV and HIV-1 MA domains.
- Depletion of PI(4,5)P2 significantly inhibited FIV particle production, confirming its essential role in FIV assembly.
Conclusions:
- FIV utilizes a myristylation-dependent membrane targeting mechanism for its Gag protein, analogous to HIV.
- FIV, like HIV, hijacks the PI(4,5)P2 cellular signaling pathway for efficient Gag trafficking and virus assembly.
- These findings highlight conserved lentiviral strategies for membrane association and provide potential targets for antiviral therapies.
