Structural basis of diverse substrate recruitment by the HIV-1 Vpr-hijacked CRL4(VprBP) E3 ligase
8 affiliations
- 1Beijing Frontier Research Center for Biological Structure, Center for Infection Biology, School of Basic Medical Sciences, Tsinghua University, Beijing, China
- 2Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
- 3Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- 4School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- 5Cryo-EM Knowledge Hub, ETH Zürich, Zürich, Switzerland
- 6Department of Chemistry, Tsinghua University, Beijing, China
- 7Tsinghua-Peking Joint Center for Life Sciences, Beijing, China
- 8SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Taiyuan, China
Abstract
HIV-1 hijacks the host CUL4-RING E3 ligase (CRL4) complex to trigger the degradation of various restriction factors. The viral accessory protein Vpr is the key protein that recruits diverse substrates to the receptor VprBP for proteasomal degradation. However, the underlying molecular mechanism remains poorly understood. Here, we characterize the molecular architecture of the DDB1-VprBP substrate recognition unit alone and in complex with different Vpr-substrates. Our results pinpoint that the LisH domain of VprBP mediates the DDB1-VprBP dimerization. Of note, the Armadillo-like (ARM-like) domains of VprBP adopt either an “up” or “down” conformation that may assist in accommodating Vpr-substrates of divergent stoichiometries and sizes. When bound to the small Vpr substrate UNG2, the two “up” ARM-like domains wrap around and directly interact with two symmetrical UNG2 molecules. Intriguingly, the ARM-like domains adopt a “down” conformation when bound to the larger TET2 fragment. Our structures highlight that the conformational dynamics of VprBP could enable the DDB1-VprBP complex to mediate the degradation of diverse Vpr-bound host factors. These findings could facilitate the structure-guided development of CRL4(VprBP)-based targeted protein degradation. Author summary: The HIV-1 accessory protein Vpr promotes the proteasomal degradation of diverse host antiviral proteins via hijacking the CRL4(VprBP) E3 ligase. Moreover, investigations of the Vpr-mediated substrate recruitment characterized the Vpr protein as a natural molecular glue and a fundamental archetype for the development of proteolysis-targeting chimeras (PROTACs). Nevertheless, the mechanism by which Vpr modulates CRL4(VprBP) E3 ligase to accommodate substrates with divergent sizes and architectures is not fully understood. By determining the cryo-EM structures of DDB1-VprBP in its apo state and in complex with two Vpr-bound substrates, we unravel a profound degree of structural plasticity within the assembly, particularly involving the Armadillo-like (ARM-like) domain of VprBP, which engages in the binding of Vpr-substrates with various sizes. For small substrates, ARM-like domains adopt an “ARM-up” conformation, which cooperates with WD40 domains to create a pocket for the binding of substrates (e.g., Vpr-UNG2). Interestingly, ARM-like domain switches to an “ARM-down” conformation to avoid steric hindrance, thereby providing sufficient space for the recruitment of larger substrates (e.g., Vpr-TET2). These findings provide mechanistic insight into how DDB1-VprBP could recognize a broad range of Vpr-bound substrates and provide a molecular basis for engineering next-generation chimeric degraders.
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BibTeX
@article{wang2026structural,
title = {{Structural basis of diverse substrate recruitment by the HIV-1 Vpr-hijacked CRL4(VprBP) E3 ligase}},
author = {Dianhong Wang and Weijia Ding and Jingwei Xu and Ruofan Li and Tamino Cairoli and Qi Liu and Yiying Zhu and Ye Xiang},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014610},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014610},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Structural basis of diverse substrate recruitment by the HIV-1 Vpr-hijacked CRL4(VprBP) E3 ligase
AU - Dianhong Wang
AU - Weijia Ding
AU - Jingwei Xu
AU - Ruofan Li
AU - Tamino Cairoli
AU - Qi Liu
AU - Yiying Zhu
AU - Ye Xiang
PY - 2026
DA - 2026/10/01
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014610
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014610
AB - HIV-1 hijacks the host CUL4-RING E3 ligase (CRL4) complex to trigger the degradation of various restriction factors. The viral accessory protein Vpr is the key protein that recruits diverse substrates to the receptor VprBP for proteasomal degradation. However, the underlying molecular mechanism remains poorly understood. Here, we characterize the molecular architecture of the DDB1-VprBP substrate recognition unit alone and in complex with different Vpr-substrates. Our results pinpoint that the LisH domain of VprBP mediates the DDB1-VprBP dimerization. Of note, the Armadillo-like (ARM-like) domains of VprBP adopt either an “up” or “down” conformation that may assist in accommodating Vpr-substrates of divergent stoichiometries and sizes. When bound to the small Vpr substrate UNG2, the two “up” ARM-like domains wrap around and directly interact with two symmetrical UNG2 molecules. Intriguingly, the ARM-like domains adopt a “down” conformation when bound to the larger TET2 fragment. Our structures highlight that the conformational dynamics of VprBP could enable the DDB1-VprBP complex to mediate the degradation of diverse Vpr-bound host factors. These findings could facilitate the structure-guided development of CRL4(VprBP)-based targeted protein degradation. Author summary: The HIV-1 accessory protein Vpr promotes the proteasomal degradation of diverse host antiviral proteins via hijacking the CRL4(VprBP) E3 ligase. Moreover, investigations of the Vpr-mediated substrate recruitment characterized the Vpr protein as a natural molecular glue and a fundamental archetype for the development of proteolysis-targeting chimeras (PROTACs). Nevertheless, the mechanism by which Vpr modulates CRL4(VprBP) E3 ligase to accommodate substrates with divergent sizes and architectures is not fully understood. By determining the cryo-EM structures of DDB1-VprBP in its apo state and in complex with two Vpr-bound substrates, we unravel a profound degree of structural plasticity within the assembly, particularly involving the Armadillo-like (ARM-like) domain of VprBP, which engages in the binding of Vpr-substrates with various sizes. For small substrates, ARM-like domains adopt an “ARM-up” conformation, which cooperates with WD40 domains to create a pocket for the binding of substrates (e.g., Vpr-UNG2). Interestingly, ARM-like domain switches to an “ARM-down” conformation to avoid steric hindrance, thereby providing sufficient space for the recruitment of larger substrates (e.g., Vpr-TET2). These findings provide mechanistic insight into how DDB1-VprBP could recognize a broad range of Vpr-bound substrates and provide a molecular basis for engineering next-generation chimeric degraders.
SN - 1553-7374
ER -