The DDB1-DCAF1-Vpr-UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction.
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.
Mesh Terms:
Carrier Proteins, Cell Line, Crystallography, X-Ray, DNA Glycosylases, DNA-Binding Proteins, HIV Infections, HIV-1, Humans, Models, Molecular, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Proteolysis, vpr Gene Products, Human Immunodeficiency Virus
Carrier Proteins, Cell Line, Crystallography, X-Ray, DNA Glycosylases, DNA-Binding Proteins, HIV Infections, HIV-1, Humans, Models, Molecular, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Proteolysis, vpr Gene Products, Human Immunodeficiency Virus
Nat. Struct. Mol. Biol.
Date: Oct. 01, 2016
PubMed ID: 27571178
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