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

Banchenko, S., Krupp, F., Gotthold, C., Bürger, J., Graziadei, A., O'Reilly, F. J., et al. (2021). Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses. PLoS Pathogens, 17(8): e1009775. doi:10.1371/journal.ppat.1009775.

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© 2021 Banchenko et al

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Banchenko, Sofia , Author
Krupp, Ferdinand, Author
Gotthold, Christine , Author
Bürger, Jörg1, 2, Author           
Graziadei, Andrea , Author
O'Reilly, Francis J., Author
Sinn, Ludwig, Author
Ruda, Olga, Author
Rappsilber, Juri , Author
Spahn , Christian M. T. , Author
Mielke, Thorsten1, Author           
Taylor, Ian A ., Author
Schwefel, David, Author
Affiliations:
1Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              
2Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2021-07-022021-08-02
 Publication Status: Published online
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 Identifiers: DOI: 10.1371/journal.ppat.1009775
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Title: PLoS Pathogens
  Other : PLoS Pathog.
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 17 (8) Sequence Number: e1009775 Start / End Page: - Identifier: ISSN: 1553-7366
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000018830