Translocation of HIV capsid core through the Nuclear Pore Complex by affinity gradient

Area of Science:

• Virology
• Cell Biology
• Structural Biology

Background:

• The HIV capsid core is essential for viral genome delivery into host cells.
• Nuclear Pore Complex (NPC) translocation is a critical step in HIV replication.
• The molecular mechanisms governing capsid core transit through the NPC are not fully understood.

Purpose of the Study:

• To investigate the molecular interactions between the HIV capsid core and phenylalanine-glycine (FG) repeats within the NPC.
• To elucidate the role of different FG repeat motifs and binding enhancers in capsid translocation.
• To understand how these interactions facilitate unidirectional nuclear entry.

Main Methods:

• Biochemical assays
• Biophysical techniques
• Structural analysis
• Quantitative interaction studies

Main Results:

• HIV capsid (CA) proteins exhibit varying affinities for diverse FG repeats.
• GLFG motifs of NUP98 show higher affinity to CA than canonical FG/FxFG motifs.
• A non-canonical FxFG motif in NUP153, termed FG super-motif, demonstrates significantly enhanced binding affinity to CA, further boosted by basic residues.
• Binding affinity increases with proximity to the NPC's nuclear basket, with a ~1,000-fold difference observed for NUP153's FG super-motif.
• NPC FG-nucleoporins NUP58 and POM121 act as binding enhancers.

Conclusions:

• A gradient of avidity, driven by diverse FG motifs and binding enhancers, exists along the cytoplasmic-nuclear axis within the NPC.
• This avidity gradient potentiates unidirectional HIV capsid translocation into the nucleus.
• Understanding these interactions offers potential targets for antiviral therapies.