6ZX9

Crystal structure of SIV Vpr,fused to T4 lysozyme, isolated from moustached monkey, bound to human DDB1 and human DCAF1 (amino acid residues 1046-1396)

Summary for 6ZX9

• Entry DOI: 10.2210/pdb6zx9/pdb
• Descriptor: DNA damage-binding protein 1, DDB1- and CUL4-associated factor 1, Vpr protein fused to T4 lysozyme, ... (6 entities in total)
• Functional Keywords: viral protein vpr, viral hijacking of human ubiquitin ligase crl4, ddb1, dcaf1, viral protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 198623.62

Authors

Schwefel, D.,Banchenko, S. (deposition date: 2020-07-29, release date: 2021-07-21, Last modification date: 2024-01-31)

Primary citation

Banchenko, S.,Krupp, F.,Gotthold, C.,Burger, J.,Graziadei, A.,O'Reilly, F.J.,Sinn, L.,Ruda, O.,Rappsilber, J.,Spahn, C.M.T.,Mielke, T.,Taylor, I.A.,Schwefel, D.
Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.
Plos Pathog., 17:e1009775-e1009775, 2021

PubMed 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.

PubMed: 34339457
DOI: 10.1371/journal.ppat.1009775

Experimental method

X-RAY DIFFRACTION (2.5197288426 Å)