Structural insights into PPP2R5A degradation by HIV-1 Vif
- 24 May 2024
- journal article
- research article
- Published by Springer Nature in Nature Structural & Molecular Biology
- Vol. 31 (10) , 1492-1501
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.Keywords
This publication has 81 references indexed in Scilit:
- Induction of APOBEC3G Ubiquitination and Degradation by an HIV-1 Vif-Cul5-SCF ComplexScience, 2003
- HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradationNature Medicine, 2003
- The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 VifNature Medicine, 2003
- HIV-1 Vif Blocks the Antiviral Activity of APOBEC3G by Impairing Both Its Translation and Intracellular StabilityMolecular Cell, 2003
- DNA Deamination Mediates Innate Immunity to Retroviral InfectionCell, 2003
- Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcriptsNature, 2003
- Hypermutation of HIV-1 DNA in the Absence of the Vif ProteinScience, 2003
- Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif proteinNature, 2002
- Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signallingBiochemical Journal, 2001
- The B56 Family of Protein Phosphatase 2A (PP2A) Regulatory Subunits Encodes Differentiation-induced Phosphoproteins That Target PP2A to Both Nucleus and CytoplasmJournal of Biological Chemistry, 1996