Synergy and allostery in ligand binding by HIV-1 Nef

Area of Science:

• Virology
• Molecular Biology
• Structural Biology

Background:

• The Nef protein of human and simian immunodeficiency viruses enhances viral pathogenicity.
• Nef interacts with host cell proteins by combining flexible regions and a structured core domain.
• Nef specifically binds to SH3 domains of Src family kinases via proline-rich motifs and hydrophobic surfaces.

Purpose of the Study:

• To investigate if Nef's flexible regions allosterically influence ligand selection through interactions with its core domain.
• To identify human proteins with similar SH3 domain selectivity as Nef using proteomic and bioinformatics analyses.

Main Methods:

• Analysis of Nef protein structure and ligand binding.
• Proteomic screening of a whole-human fetal library.
• Bioinformatic analysis of protein-protein interactions.

Main Results:

• Nef's flexible regions can adopt distinct conformational states, altering SH3 domain selection and binding motif exposure.
• Only 3% of human proteins exhibited Nef-like SH3 selectivity, primarily through canonical linear interactions, not Nef-like tertiary interactions.
• Nef's SH3 domain hijacking mechanism appears to be a virus-specific adaptation.

Conclusions:

• Nef's unique tertiary binding surface is a virus-specific adaptation with limited cellular counterparts.
• The Nef tertiary binding surface represents a promising target for developing novel antiviral therapies.