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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. In conclusion, Vpr uses molecular mimicry of DNA by a variable loop for specific recruitment of the UNG2 substrate.

Authors:
 [1];  [1];  [1];  [1];  [2];  [1];  [1];  [1]
  1. Univ. of Pittsburgh, PA (United States)
  2. Stanford Univ., Menlo Park, CA (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Inst. of Health; National Inst. of General Medical Sciences
OSTI Identifier:
1330269
Grant/Contract Number:  
AC02-76SF00515; P41GM103393; P50GM082251
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 23; Journal Issue: 10; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; virology; X-ray crystallography

Citation Formats

Wu, Ying, Zhou, Xiaohong, Barnes, Christopher O., DeLucia, Maria, Cohen, Aina E., Gronenborn, Angela M., Ahn, Jinwoo, and Calero, Guillermo. The DDB1–DCAF1–Vpr–UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction. United States: N. p., 2016. Web. doi:10.1038/nsmb.3284.
Wu, Ying, Zhou, Xiaohong, Barnes, Christopher O., DeLucia, Maria, Cohen, Aina E., Gronenborn, Angela M., Ahn, Jinwoo, & Calero, Guillermo. The DDB1–DCAF1–Vpr–UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction. United States. https://doi.org/10.1038/nsmb.3284
Wu, Ying, Zhou, Xiaohong, Barnes, Christopher O., DeLucia, Maria, Cohen, Aina E., Gronenborn, Angela M., Ahn, Jinwoo, and Calero, Guillermo. 2016. "The DDB1–DCAF1–Vpr–UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction". United States. https://doi.org/10.1038/nsmb.3284. https://www.osti.gov/servlets/purl/1330269.
@article{osti_1330269,
title = {The DDB1–DCAF1–Vpr–UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction},
author = {Wu, Ying and Zhou, Xiaohong and Barnes, Christopher O. and DeLucia, Maria and Cohen, Aina E. and Gronenborn, Angela M. and Ahn, Jinwoo and Calero, Guillermo},
abstractNote = {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. In conclusion, Vpr uses molecular mimicry of DNA by a variable loop for specific recruitment of the UNG2 substrate.},
doi = {10.1038/nsmb.3284},
url = {https://www.osti.gov/biblio/1330269}, journal = {Nature Structural & Molecular Biology},
issn = {1545-9993},
number = 10,
volume = 23,
place = {United States},
year = {Mon Aug 29 00:00:00 EDT 2016},
month = {Mon Aug 29 00:00:00 EDT 2016}
}

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Works referencing / citing this record:

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?
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Is Uracil-DNA Glycosylase UNG2 a New Cellular Weapon Against HIV-1?
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Illuminating the Role of Vpr in HIV Infection of Myeloid Cells
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The HIV-1 Vpr Protein: A Multifaceted Target for Therapeutic Intervention
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CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation
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Mannose receptor is an HIV restriction factor counteracted by Vpr in macrophages
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Proteasomal Degradation Machinery: Favorite Target of HIV-1 Proteins
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CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation
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New paradigm of functional regulation by DNA mimic proteins: Recent updates
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Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins
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Vpr and Its Cellular Interaction Partners: R We There Yet?
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Proteasomal Degradation Machinery: Favorite Target of HIV-1 Proteins
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Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex
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HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence
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Distinct MCM10 Proteasomal Degradation Profiles by Primate Lentiviruses Vpr Proteins
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A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?
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Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins
journal, October 2017


Vpr and Its Cellular Interaction Partners: R We There Yet?
journal, October 2019


WD40 repeat domain proteins: a novel target class?
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