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Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses

DOI: 10.1371/journal.ppat.1009775 DOI Help

Authors: Sofia Banchenko (Charité-Universitätsmedizin Berlin; Freie Universität Berlin and Humboldt-Universität zu Berlin) , Ferdinand Krupp (Charité-Universitätsmedizin Berlin; Freie Universität Berlin and Humboldt-Universität zu Berlin) , Christine Gotthold (Charité-Universitätsmedizin Berlin; Freie Universität Berlin and Humboldt-Universität zu Berlin) , Jörg Bürger (Charité-Universitätsmedizin Berlin; Freie Universität Berlin and Humboldt-Universität zu Berlin; Max-Planck-Institute for Molecular Genetics) , Andrea Graziadei (Technische Universität Berlin) , Francis O'Reilly (Technische Universität Berlin) , Ludwig Sinn (Technische Universität Berlin) , Olga Ruda (Charité-Universitätsmedizin Berlin; Freie Universität Berlin and Humboldt-Universität zu Berlin) , Juri Rappsilber (Technische Universität Berlin) , Christian M. T. Spahn (Charité-Universitätsmedizin Berlin; Freie Universität Berlin and Humboldt-Universität zu Berlin) , Thorsten Mielke (Max-Planck-Institute for Molecular Genetics) , Ian A. Taylor (The Francis Crick Institute) , David Schwefel (Charité-Universitätsmedizin Berlin; Freie Universität Berlin and Humboldt-Universität zu Berlin)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Pathogens , VOL 17

State: Published (Approved)
Published: August 2021

Open Access Open Access

Abstract: Viruses have evolved means to manipulate the host’s ubiquitin-proteasome system, in order to down-regulate antiviral host factors. The Vpx/Vpr family of lentiviral accessory proteins usurp the substrate receptor DCAF1 of host Cullin4-RING ligases (CRL4), a family of modular ubiquitin ligases involved in DNA replication, DNA repair and cell cycle regulation. CRL4DCAF1 specificity modulation by Vpx and Vpr from certain simian immunodeficiency viruses (SIV) leads to recruitment, poly-ubiquitylation and subsequent proteasomal degradation of the host restriction factor SAMHD1, resulting in enhanced virus replication in differentiated cells. To unravel the mechanism of SIV Vpr-induced SAMHD1 ubiquitylation, we conducted integrative biochemical and structural analyses of the Vpr protein from SIVs infecting Cercopithecus cephus (SIVmus). X-ray crystallography reveals commonalities between SIVmus Vpr and other members of the Vpx/Vpr family with regard to DCAF1 interaction, while cryo-electron microscopy and cross-linking mass spectrometry highlight a divergent molecular mechanism of SAMHD1 recruitment. In addition, these studies demonstrate how SIVmus Vpr exploits the dynamic architecture of the multi-subunit CRL4DCAF1 assembly to optimise SAMHD1 ubiquitylation. Together, the present work provides detailed molecular insight into variability and species-specificity of the evolutionary arms race between host SAMHD1 restriction and lentiviral counteraction through Vpx/Vpr proteins.

Journal Keywords: Electron cryo-microscopy; Crystal structure; SIV; Magnesium chloride; Protein complexes; Amino acid analysis; Proteases; Viral replication

Diamond Keywords: Viruses

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: I04-Macromolecular Crystallography , Krios I-Titan Krios I at Diamond

Other Facilities: BL14.1, BL14.2, and BL14.3 at BESSY II; ID30A-3, ID30B, ID23-1, ID23-2, and ID29 at ESRF

Added On: 05/10/2021 09:36

Documents:
journal.ppat.1009775.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Infectious Diseases Pathogens Structural biology

Technical Tags:

Microscopy Macromolecular Crystallography (MX) Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)