Structural basis for GTP-induced dimerization and antiviral function of guanylate-binding proteins.

Area of Science:

• Structural biology
• Innate immunity
• Virology

Background:

• Guanylate-binding proteins (GBPs) are large GTPases involved in innate immunity.
• Their oligomerization mechanism upon GTP binding is poorly understood.
• GBPs play a role in antiviral defense, including against HIV-1.

Purpose of the Study:

• To elucidate the molecular mechanism of guanylate-binding protein (GBP) oligomerization.
• To determine the structural basis of GBP-mediated inhibition of HIV-1.
• To investigate the conserved dimerization mode of GBPs.

Main Methods:

• X-ray crystallography of human GBP5 (hGBP5) and human GBP2 (hGBP2).
• Structural analysis of nucleotide-free monomeric and nucleotide-bound dimeric states.
• Functional assays assessing HIV-1 inhibition upon disruption of GBP interfaces.

Main Results:

• Crystal structures revealed a GTP-induced face-to-face dimerization of hGBP5.
• The middle domain (MD) of hGBP5 undergoes significant rearrangement upon dimerization.
• Disruption of the MD interface or hinge region mutations impaired HIV-1 inhibition.

Conclusions:

• A conserved GTP-induced dimerization mechanism is proposed for GBPs.
• GBP dimerization is essential for their antiviral activity against HIV-1.
• Structural insights into GBP function provide a basis for understanding innate immune responses.