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

Wu, Ying; Zhou, Xiaohong; Barnes, Christopher O.; DeLucia, Maria; Cohen, Aina E.; Gronenborn, Angela M.; Ahn, Jinwoo; Calero, Guillermo

doi:10.1038/nsmb.3284

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

Journal Article · Mon Aug 29 00:00:00 EDT 2016 · Nature Structural & Molecular Biology

DOI:https://doi.org/10.1038/nsmb.3284· OSTI ID:1330269

Wu, Ying ^[1]; Zhou, Xiaohong ^[1]; Barnes, Christopher O. ^[1]; DeLucia, Maria ^[1]; Cohen, Aina E. ^[2]; Gronenborn, Angela M. ^[1]; Ahn, Jinwoo ^[1]; Calero, Guillermo ^[1]

Univ. of Pittsburgh, PA (United States)
Stanford Univ., Menlo Park, CA (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: 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

Grant/Contract Number:: AC02-76SF00515; P41GM103393; P50GM082251

OSTI ID:: 1330269

Journal Information:: Nature Structural & Molecular Biology, Vol. 23, Issue 10; ISSN 1545-9993

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 59 works

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