title: The DDB1-DCAF1-Vpr-UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction.
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.
authors: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Ying
authors: Y
authors: Wu
authors: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Xiaohong
authors: X
authors: Zhou
authors: Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Christopher O
authors: CO
authors: Barnes
authors: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Maria
authors: M
authors: DeLucia
authors: Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, California, USA.
authors: Aina E
authors: AE
authors: Cohen
authors: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Angela M
authors: AM
authors: Gronenborn
authors: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Jinwoo
authors: J
authors: Ahn
authors: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Guillermo
authors: G
authors: Calero
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D018360:Crystallography, X-Ray; D045647:DNA Glycosylases / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D044767:Ubiquitin-Protein Ligases; C530533:DCAF1 protein, human; D017346:Protein Serine-Threonine Kinases; C492570:CCNO protein, human; D045647:DNA Glycosylases