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Nat Struct Mol Biol. 2016 Oct;23(10):933-940. doi: 10.1038/nsmb.3284. Epub 2016 Aug 29.

The DDB1-DCAF1-Vpr-UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction.

Author information

1
Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
2
Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
3
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
4
Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, California, USA.

Abstract

The HIV-1 accessory protein Vpr is required for efficient viral infection of macrophages and promotion of viral replication in T cells. Vpr's biological activities are closely linked to the interaction with human DCAF1, a cellular substrate receptor of the Cullin4-RING E3 ubiquitin ligase (CRL4) of the host ubiquitin-proteasome-mediated protein degradation pathway. The molecular details of how Vpr usurps the protein degradation pathway have not been delineated. Here we present the crystal structure of the DDB1-DCAF1-HIV-1-Vpr-uracil-DNA glycosylase (UNG2) complex. The structure reveals how Vpr engages with DCAF1, creating a binding interface for UNG2 recruitment in a manner distinct from the recruitment of SAMHD1 by Vpx proteins. Vpr and Vpx use similar N-terminal and helical regions to bind the substrate receptor, whereas different regions target the specific cellular substrates. Furthermore, Vpr uses molecular mimicry of DNA by a variable loop for specific recruitment of the UNG2 substrate.

PMID:
27571178
PMCID:
PMC5385928
DOI:
10.1038/nsmb.3284
[Indexed for MEDLINE]
Free PMC Article

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