Adeno-associated virus 2 bound to its cellular receptor AAVR

Area of Science:

• Structural biology
• Virology
• Gene therapy

Background:

• Adeno-associated virus (AAV) is a key vector for gene therapy.
• Understanding AAV-receptor interactions is vital for optimizing gene delivery vectors.
• The Adeno-associated virus receptor (AAVR) was recently identified.

Purpose of the Study:

• To determine the high-resolution cryo-electron microscopy structure of the Adeno-associated virus type 2 (AAV2)-AAVR complex.
• To elucidate the molecular details of AAV-AAVR recognition.
• To provide insights for engineering improved AAV vectors.

Main Methods:

• Cryo-electron microscopy (cryo-EM) at 2.8 Å resolution.
• Particle-filtering algorithm for structure determination.
• Site-directed mutagenesis to assess binding and infectivity.

Main Results:

• The structure reveals that the PKD2 domain of AAVR directly binds to the spike region of the AAV2 capsid near the three-fold axis.
• Specific residues in AAVR PKD2 (strands B and E, BC loop) and AAV2 capsid variable regions mediate the interaction.
• Mutagenesis of interacting residues significantly reduced AAV2-AAVR binding and viral infectivity.

Conclusions:

• The study provides high-resolution structural insights into AAV2-AAVR complex formation.
• This detailed understanding of the AAV entry mechanism opens avenues for developing novel AAV gene therapy vectors.
• The findings are critical for advancing the safety and efficacy of AAV-based gene therapies.