| 2021 |
Crystal structures of ZYG11B bound to various Gly/N-degrons reveal that ZYG11B uses its armadillo (ARM) repeats to form a deep and narrow cavity that engages mainly the first four residues of Gly/N-degrons, with the α-amino group of the degron accommodated in an acidic pocket via five conserved hydrogen bonds, establishing the structural basis for specific Gly/N-degron recognition by the CRL2ZYG11B E3 ubiquitin ligase complex. |
X-ray crystallography of ZYG11B bound to Gly/N-degron peptides, combined with biochemical binding assays |
Molecular cell |
High |
34214466
|
| 2021 |
SARS-CoV-2 ORF10 physically interacts with ZYG11B (the substrate receptor of CRL2ZYG11B), and the N-terminus of ORF10 is critical for this interaction; however, ORF10 does not function to inhibit or hijack CRL2ZYG11B, and ZYG11B (and its paralog ZER1) are dispensable for SARS-CoV-2 infection in cultured cells. |
Co-immunoprecipitation, N-terminal deletion analysis, ZYG11B/ZER1 knockout cell infection assays |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
33827988
|
| 2020 |
A truncating mutation in ZYG11B (p.Glu537*) produces a protein with altered subcellular localization in HeLa cells compared to wild-type ZYG11B; knockdown of the zebrafish ZYG11B homologue disrupts craniofacial cartilage architecture and notochord development, and ZYG11B expression regulates the cartilage master regulator SOX6 and is regulated by retinoic acid. |
Overexpression and immunofluorescence of wild-type vs. mutant ZYG11B in HeLa cells; morpholino-based knockdown in zebrafish embryos with phenotypic readout; RT-qPCR for SOX6 |
Molecular genetics & genomic medicine |
Medium |
32738032
|
| 2022 |
ZYG11B (as part of CRL2ZYG11B) recognizes not only N-terminal glycine but also small Nt-residues (Ser, Ala, Cys) in vitro; however, Nt-acetylation of Ser, Ala, and Cys by N-terminal acetyltransferases (NATs) shields these residues from ZYG11B recognition in cells, while in NAT-deficient cells ZYG11B/ZER1 targets these unacetylated small Nt-residues for proteasomal degradation. Crystal structures of ZYG11B bound to these small Nt-residues reveal the molecular mechanism of non-acetylated substrate recognition. |
In vitro binding assays, cellular degradation assays in NAT-deficient cells, X-ray crystallography |
Nature communications |
High |
36496439
|
| 2023 |
ZYG11B acts as an amplifier of cGAS-mediated innate immune signaling by enhancing cGAS-DNA binding affinity, potentiating cGAS-DNA condensation, and stabilizing the cGAS-DNA condensed complex, thereby promoting cGAMP production and downstream interferon/cytokine transcription; knockdown of ZYG11B impairs these responses. Additionally, HSV-1 infection induces ZYG11B degradation in a cGAS-independent manner. |
ZYG11B knockdown with cGAMP measurement, co-immunoprecipitation/pulldown for cGAS-DNA-ZYG11B interaction, condensation assays, HSV-1 infection assays |
Cell reports |
Medium |
36933219
|
| 2022 |
Crystal structure of ZYG11B bound to the N-terminal peptide of SARS-CoV-2 ORF10 reveals the structural basis for recognition of the ORF10 N-terminus by ZYG11B's substrate-binding cavity. |
X-ray crystallography of ZYG11B–ORF10 N-terminal peptide complex |
Biochemical and biophysical research communications |
Medium |
35636250
|
| 2025 |
ZYG11B, as part of the CRL2ZYG11B complex, targets Enterovirus 71 (EV71) structural protein VP1 for proteasomal degradation via K33-linked ubiquitination; mass spectrometry and immunoprecipitation confirmed the ZYG11B–VP1 interaction and identified key domains on ZYG11B required for VP1 binding and CUL2 recruitment. ZYG11B also restricts related enteroviruses (CA6, CA16, EVD68) whose VP1 ubiquitination sites are highly conserved. |
Mass spectrometry, co-immunoprecipitation, domain mapping, proteasome inhibitor assays, K33 ubiquitination linkage analysis, viral replication functional assays |
Journal of virology |
Medium |
40135890
|
| 2026 |
Cryo-EM structures of full-length human ZYG11B in complex with EloB-EloC adaptor and a Gly/N-degron peptide reveal a seahorse-like architecture with distinct interfaces for adaptor binding and substrate engagement. ZYG11B adopts both monomeric and dimeric assemblies, with the dimer stabilizing two substrate-binding sites in opposite orientations. Functional assays demonstrate that interfaces mediating adaptor recruitment, substrate binding, and dimerization are all essential for substrate degradation. |
Cryo-EM structure determination of full-length ZYG11B–EloB–EloC–substrate complex; mutagenesis of assembly interfaces with substrate degradation functional assays |
Nature communications |
High |
41917018
|
| 2024 |
Cryo-EM structures of the full CRL2-ZYG11B holoenzyme alone and in complex with a Gly/N-degron peptide from NLRP1 reveal that ZYG11B folds into a Leucine-Rich Repeat domain followed by two armadillo repeat domains that mediate CRL2 assembly and NLRP1 Gly/N-degron recognition. ZYG11B promotes NLRP1 inflammasome activation by recognizing and ubiquitinating the Gly/N-degron exposed after viral protease cleavage of NLRP1; blocking ZYG11B recognition of this degron inhibits viral protease-mediated NLRP1 inflammasome activation. |
Cryo-EM structure of CRL2-ZYG11B holoenzyme ± Gly/N-degron peptide; in vitro ubiquitination assays; functional inflammasome activation assays with blocking experiments |
bioRxivpreprint |
Medium |
bio_10.1101_2024.06.24.600508
|
| 2025 |
A non-inhibitory DNA aptamer targeting ZYG11B was identified and validated as an E3 ligase warhead for PROTAC-based targeted protein degradation (ZATAC platform), demonstrating that ZYG11B can be recruited to degrade diverse neo-substrates (nucleolin, SOX2, mutant p53-R175H) when bridged via an aptamer, and that cancer-cell-targeted 3WJ-ZATACs achieve dual-target degradation and suppress tumor growth in vivo without noticeable toxicity. |
Aptamer selection and binding validation; PROTAC/ZATAC functional degradation assays for multiple target proteins; in vivo tumor xenograft experiments |
Nature communications |
Medium |
40082426
|