Structural basis of chimpanzee APOBEC3H dimerization stabilized by double-stranded RNA

Area of Science:

• Structural Biology
• Virology
• Molecular Biology

Background:

• APOBEC3H (A3H) is a primate-specific cytidine deaminase crucial for restricting retroviral replication.
• Primate A3Hs play a role in preventing cross-species transmission of primate immunodeficiency viruses.
• The molecular structures and mechanisms of primate A3Hs remain incompletely understood.

Purpose of the Study:

• To determine the crystal structure of chimpanzee A3H (cpzA3H) dimer bound to double-stranded RNA (dsRNA).
• To elucidate the structural basis for dsRNA binding and sequence preference.
• To investigate the role of dsRNA interaction in cpzA3H stability and regulation.

Main Methods:

• X-ray crystallography to determine the 2.20-Å structure of cpzA3H dimer bound to dsRNA.
• Biochemical analysis of dsRNA-binding interface and sequence specificity.
• Cellular assays to assess the impact of mutations on protein stability and proteasomal degradation.

Main Results:

• The crystal structure reveals a specialized dsRNA-binding interface in cpzA3H.
• cpzA3H exhibits a sequence preference for GC-rich, palindrome-like dsRNA, mediated by arginine residues in loop 1.
• Mutations affecting dsRNA interaction lead to reduced cpzA3H stability and increased proteasomal degradation.

Conclusions:

• The study provides high-resolution structural insights into primate A3H-dsRNA interactions.
• cpzA3H stability is regulated by dsRNA binding and cellular proteasomal degradation pathways.
• These findings enhance understanding of primate A3H function and regulation in cellular antiviral defense.