9E9V

Structural Insights into HIV-1 Vif-Mediated Ubiquitination and Degradation of APOBEC3H

Summary for 9E9V

• Entry DOI: 10.2210/pdb9e9v/pdb
• Related: 9E93
• EMDB information: 47805
• Descriptor: single-stranded DNA cytosine deaminase, RNA (5'-R(P*CP*CP*CP*GP*GP*CP*A)-3'), RNA (5'-R(P*GP*CP*CP*GP*GP*G)-3'), ... (8 entities in total)
• Functional Keywords: apobec3h hiv-1 vif, viral protein, viral protein-rna complex, viral protein/rna
• Biological source: Pan troglodytes (chimpanzee); More
• Total number of polymer chains: 13
• Total formula weight: 182502.83

Authors

Matsuo, H.,Skorupka, K.A. (deposition date: 2024-11-08, release date: 2026-03-11)

Primary citation

Skorupka, K.A.,Matsuoka, K.,Hassan, B.,Ghirlando, R.,Balachandran, V.,Chen, T.H.,Walters, K.J.,Schiffer, C.A.,Wolf, M.,Iwatani, Y.,Matsuo, H.
HIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradation.
Nat Commun, 16:5879-5879, 2025

PubMed Abstract: The APOBEC3 family of cytidine deaminases restricts retroviruses like HIV-1 by mutating viral DNA. HIV-1 evades this restriction by producing Vif, which recruits the Cullin-5 (CUL5) E3 ubiquitin ligase complex to promote APOBEC3 degradation. Here we resolve key aspects of this counter-defense mechanism by determining a 3.6 Å cryo-EM structure of chimpanzee APOBEC3H (cpzA3H) in complex with HIV-1 Vif and three components of the CUL5 E3 ligase-CBFβ, EloB, and EloC (VCBC). The structure captures cpzA3H as an RNA-mediated dimer within the cpzA3H-VCBC complex, allowing us to examine the role of dimerization. We find that ubiquitination occurs specifically at two lysine residues on the Vif-proximal protomer, while the distal protomer remains unmodified. The structural model of the active cpzA3H-Vif-CUL5 E3 ligase holoenzyme reveals spatial preferences for ubiquitin transfer to the targeted lysine residues. These findings enhance our understanding of A3H degradation and suggest new antiviral strategies targeting this host-virus interface.

PubMed: 40593686
DOI: 10.1038/s41467-025-60984-y

Experimental method

ELECTRON MICROSCOPY (4 Å)