8SZK

The cryo-EM structure of PPP2R5A/HIV-1 Vif/CBFb/EloB/EloC complex

Summary for 8SZK

• Entry DOI: 10.2210/pdb8szk/pdb
• EMDB information: 40919
• Descriptor: Elongin-B, Elongin-C, Core-binding factor subunit beta, ... (5 entities in total)
• Functional Keywords: hiv vif, cul5 e3 ligase, ppp2r5a, viral protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 124884.19

Authors

Hu, Y.,Xiong, Y. (deposition date: 2023-05-30, release date: 2024-06-05, Last modification date: 2025-05-28)

Primary citation

Hu, Y.,Delviks-Frankenberry, K.A.,Wu, C.,Arizaga, F.,Pathak, V.K.,Xiong, Y.
Structural insights into PPP2R5A degradation by HIV-1 Vif.
Nat.Struct.Mol.Biol., 31:1492-1501, 2024

PubMed Abstract: HIV-1 Vif recruits host cullin-RING-E3 ubiquitin ligase and CBFβ to degrade the cellular APOBEC3 antiviral proteins through diverse interactions. Recent evidence has shown that Vif also degrades the regulatory subunits PPP2R5(A-E) of cellular protein phosphatase 2A to induce G2/M cell cycle arrest. As PPP2R5 proteins bear no functional or structural resemblance to A3s, it is unclear how Vif can recognize different sets of proteins. Here we report the cryogenic-electron microscopy structure of PPP2R5A in complex with HIV-1 Vif-CBFβ-elongin B-elongin C at 3.58 Å resolution. The structure shows PPP2R5A binds across the Vif molecule, with biochemical and cellular studies confirming a distinct Vif-PPP2R5A interface that partially overlaps with those for A3s. Vif also blocks a canonical PPP2R5A substrate-binding site, indicating that it suppresses the phosphatase activities through both degradation-dependent and degradation-independent mechanisms. Our work identifies critical Vif motifs regulating the recognition of diverse A3 and PPP2R5A substrates, whereby disruption of these host-virus protein interactions could serve as potential targets for HIV-1 therapeutics.

PubMed: 38789685
DOI: 10.1038/s41594-024-01314-6

Experimental method

ELECTRON MICROSCOPY (3.58 Å)