Affinage

ZYG11B

Protein zyg-11 homolog B · UniProt Q9C0D3

Length
744 aa
Mass
83.9 kDa
Annotated
2026-04-28
16 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZYG11B is the substrate-recognition subunit of the CRL2^ZYG11B E3 ubiquitin ligase, functioning as the principal N-recognin of the Gly/N-degron pathway to target proteins bearing unacetylated N-terminal glycine—and other small N-terminal residues (Ser, Ala, Cys)—for proteasomal degradation (PMID:34214466, PMID:36496439). ZYG11B binds EloB/EloC adaptors through a VHL-box motif and engages substrates via its armadillo repeat domain, which forms a deep acidic pocket that hydrogen-bonds the free α-amino group of the N-terminal glycine; full-length ZYG11B adopts a seahorse-like architecture and can dimerize to present two substrate-binding sites, with all three interfaces—adaptor recruitment, substrate binding, and dimerization—required for degradation (PMID:17304241, PMID:34214466, PMID:41917018). Physiological substrates include meiotic cyclin B in C. elegans, the NLRP1 inflammasome sensor after viral protease cleavage, and enterovirus EV71 VP1, while ZYG11B also enhances cGAS-DNA condensation to amplify innate immune signaling independently of its E3 ligase activity (PMID:15215208, PMID:40135890, PMID:36933219). A truncating ZYG11B mutation disrupts protein localization, and zebrafish knockdown causes craniofacial cartilage and notochord defects linked to SOX6 dysregulation (PMID:32738032).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 High

    Establishing ZYG-11 as a CUL-2-linked cell-cycle regulator answered the question of how meiosis II metaphase-to-anaphase transition is controlled in C. elegans embryos, revealing cyclin B as a degradation target and an additional role in anterior-posterior polarity.

    Evidence RNAi knockdown and genetic epistasis in C. elegans embryos, live imaging of PAR proteins and P granules

    PMID:15215208 PMID:15215209

    Open questions at the time
    • Direct biochemical interaction between ZYG-11 and cyclin B not demonstrated
    • Whether polarity function requires ubiquitin ligase activity or acts through a separate mechanism
    • Mammalian homolog function unknown
  2. 2007 High

    Demonstrating that ZYG-11 directly binds CUL-2 and Elongin C via a VHL-box motif established ZYG11 family proteins as bona fide CRL2 substrate-recognition subunits conserved from nematodes to humans.

    Evidence Reciprocal co-immunoprecipitation in vivo, VHL-box motif identification and cross-species sequence analysis

    PMID:17304241

    Open questions at the time
    • No substrate identified for the mammalian ZYG11B paralog
    • Structural basis of adaptor and substrate engagement unknown
  3. 2020 Medium

    A human truncating ZYG11B mutation and zebrafish knockdown linked ZYG11B to craniofacial cartilage and notochord development, revealing a vertebrate developmental function and SOX6 as a downstream regulated gene.

    Evidence Immunofluorescence of mutant protein in HeLa cells, morpholino knockdown in zebrafish, RT-PCR

    PMID:32738032

    Open questions at the time
    • Whether SOX6 regulation is direct (i.e., SOX6 is a ubiquitination substrate) or indirect
    • Single lab, no independent replication of zebrafish phenotype
    • Mechanism connecting ZYG11B E3 ligase activity to cartilage morphogenesis not defined
  4. 2021 High

    Crystal structures of ZYG11B bound to Gly/N-degron peptides solved the long-standing question of how the CRL2^ZYG11B complex selects substrates, revealing a narrow ARM-repeat cavity that specifically accommodates the unmodified α-amino group of N-terminal glycine through five conserved hydrogen bonds.

    Evidence Crystal structure determination with multiple Gly/N-degron peptides, biochemical binding assays

    PMID:34214466

    Open questions at the time
    • Whether additional sequence context beyond the first four residues influences substrate selectivity in vivo
    • Full-length ZYG11B architecture not yet resolved
  5. 2021 High

    Testing the hypothesis that SARS-CoV-2 ORF10 hijacks CRL2^ZYG11B showed that while ORF10 binds ZYG11B via its N-terminus consistent with Gly/N-degron recognition, it neither co-opts nor inhibits the ligase, and ZYG11B is dispensable for infection.

    Evidence Co-immunoprecipitation, N-terminal deletion mapping, ZYG11B/ZER1 knockout cell infection assays, proteomics

    PMID:33827988

    Open questions at the time
    • Whether ORF10 binding has functional consequences in non-cultured-cell contexts
    • Whether ORF10 is degraded by CRL2^ZYG11B in vivo
  6. 2022 High

    Expanding the substrate specificity of ZYG11B beyond glycine to include unacetylated Nt-Ser, Nt-Ala, and Nt-Cys established CRL2^ZYG11B as a quality-control mechanism that degrades proteins escaping N-terminal acetylation.

    Evidence Crystal structures of ZYG11B with various small-residue peptides, in vitro binding assays, NAT-deficient cell degradation assays

    PMID:36496439

    Open questions at the time
    • Endogenous substrates accumulating in NAT-deficient cells due to ZYG11B have not been comprehensively catalogued
    • Relative contribution of ZYG11B versus ZER1 to Nt-acetylation quality control unclear
  7. 2023 Medium

    Demonstrating that ZYG11B enhances cGAS-DNA condensation and cGAMP production revealed an unexpected innate immunity function apparently independent of its canonical E3 ligase role, with HSV-1 degrading ZYG11B as a countermeasure.

    Evidence ZYG11B knockdown, cGAMP measurement, co-immunoprecipitation, DNA binding affinity and condensation assays, HSV-1 infection

    PMID:36933219

    Open questions at the time
    • Whether ZYG11B's ubiquitin ligase activity contributes to cGAS regulation not resolved
    • Mechanism by which HSV-1 targets ZYG11B for degradation not identified
    • Not independently replicated
  8. 2025 Medium

    Identification of enterovirus VP1 as a ZYG11B substrate demonstrated that CRL2^ZYG11B serves as an antiviral E3 ligase mediating K33-linked ubiquitination and proteasomal degradation of a viral structural protein.

    Evidence Mass spectrometry, immunoprecipitation, ubiquitination assays with linkage typing, proteasome inhibition, domain mapping

    PMID:40135890

    Open questions at the time
    • Whether VP1 targeting depends on a Gly/N-degron or an alternative recognition mode not clarified
    • In vivo antiviral significance not tested in animal models
    • Single lab study
  9. 2026 High

    Cryo-EM structures of full-length human ZYG11B–EloBC with substrate peptide resolved the overall seahorse-like architecture and revealed functionally essential dimerization, showing that two substrate-binding sites in opposing orientations are required for efficient degradation.

    Evidence Cryo-EM of monomeric and dimeric assemblies, mutagenesis of adaptor, substrate, and dimer interfaces with degradation assays

    PMID:41917018

    Open questions at the time
    • Physiological significance of dimer versus monomer in cells not established
    • No structure of a full substrate (rather than peptide) bound to the holoenzyme

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the comprehensive identification of endogenous Gly/N-degron substrates in mammalian cells, the functional division of labor between ZYG11B and its paralog ZER1, whether ZYG11B dimerization is regulated, and the molecular mechanism by which ZYG11B enhances cGAS condensation independently of ubiquitination.
  • Systematic substrate catalogue for mammalian ZYG11B lacking
  • ZYG11B vs ZER1 functional redundancy and specificity unresolved
  • Regulation of ZYG11B expression, stability, and dimerization poorly understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2
Partners
CGASCUL2ELOBELOCNLRP1VP1
Complex memberships
CRL2^ZYG11B (CUL2-EloB-EloC-ZYG11B)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 C. elegans ZYG-11 acts as a component of a CUL-2-based E3 ubiquitin ligase that promotes the metaphase-to-anaphase transition at meiosis II by targeting cyclin B (CYB-3) for degradation; inactivation of ZYG-11 leads to CYB-3 accumulation and M phase arrest. RNAi knockdown in C. elegans, genetic epistasis, cyclin B accumulation assays Development High 15215208 15215209
2004 ZYG-11 and CUL-2 regulate embryonic anterior-posterior polarity establishment in C. elegans, with their inactivation causing inverted PAR protein and P granule polarity; this polarity role can operate independently of their cell cycle progression function. RNAi knockdown, live imaging of PAR proteins and P granules in C. elegans embryos Development High 15215208 15215209
2007 ZYG-11 is the substrate-recognition subunit of a CUL-2-based ubiquitin ligase complex; it interacts with CUL-2 in vivo and binds the adaptor protein Elongin C via a nematode variant of the VHL-box motif, establishing ZYG11 family members as conserved CUL2 complex substrate receptors in nematodes and humans. Co-immunoprecipitation in vivo, VHL-box motif identification, sequence analysis of ZYG11 family across metazoa EMBO reports High 17304241
2021 ZYG11B recognizes N-terminal glycine degrons (Gly/N-degrons) via its armadillo (ARM) repeat domain, which forms a deep, narrow cavity engaging the first four residues of the degron; the α-amino group of the glycine is accommodated by five conserved hydrogen bonds in an acidic pocket. Crystal structure of ZYG11B bound to Gly/N-degron peptides, biochemical binding assays Molecular cell High 34214466
2021 SARS-CoV-2 ORF10 interacts with ZYG11B (the substrate receptor of CRL2ZYG11B) through its N-terminus, which is critical for binding; however, ORF10 does not hijack or inhibit CRL2ZYG11B activity and ZYG11B/ZER1 are dispensable for SARS-CoV-2 infection in cultured cells. Co-immunoprecipitation, N-terminal deletion mapping, ZYG11B/ZER1 knockout cell infection assays, proteomics PNAS High 33827988
2022 ZYG11B (and ZER1) can recognize small N-terminal residues beyond glycine, including Nt-Ser, Nt-Ala, and Nt-Cys in vitro; Nt-acetylation of these residues by N-terminal acetyltransferases (NATs) shields them from ZYG11B recognition, revealing a role for CRL2ZYG11B in Nt-acetylation quality control. In vitro binding assays, crystal structures of ZYG11B bound to various small Nt-residue peptides, NAT-deficient cell degradation assays Nature communications High 36496439
2022 Crystal structure of ZYG11B bound to the SARS-CoV-2 ORF10 N-terminal peptide reveals the molecular basis for ORF10 recognition by the ARM repeat domain of ZYG11B, consistent with Gly/N-degron recognition mechanism. Crystal structure determination of ZYG11B–ORF10 peptide complex Biochemical and biophysical research communications High 35636250
2023 ZYG11B enhances cGAS-mediated innate immune responses by increasing cGAS-DNA binding affinity, potentiating cGAS-DNA condensation, and stabilizing the cGAS-DNA condensed complex; ZYG11B knockdown impairs cGAMP production and downstream interferon/cytokine transcription. Additionally, HSV-1 infection induces ZYG11B degradation to dampen this response. ZYG11B knockdown with cGAMP measurement, co-immunoprecipitation, DNA binding affinity assays, condensation assays, HSV-1 infection experiments Cell reports Medium 36933219
2025 ZYG11B targets enterovirus EV71 structural protein VP1 for proteasomal degradation via the CRL2ZYG11B complex, driving K33-linked ubiquitination of VP1; the interaction between ZYG11B and VP1 was confirmed by mass spectrometry and immunoprecipitation, and key domains for VP1 and CUL2 binding were identified. Mass spectrometry, immunoprecipitation, ubiquitination assays, proteasome inhibition, domain mapping Journal of virology Medium 40135890
2026 Cryo-EM structures of full-length human ZYG11B in complex with EloB-EloC adaptor and Gly/N-degron peptide reveal a seahorse-like architecture with distinct interfaces for adaptor binding and substrate engagement; ZYG11B can form both monomeric and dimeric assemblies, with the dimer stabilizing two substrate-binding sites in opposite orientations, and functional assays show all three interfaces (adaptor recruitment, substrate binding, dimerization) are essential for substrate degradation. Cryo-EM structure determination, functional ubiquitination/degradation assays with interface mutants Nature communications High 41917018
2024 Cryo-EM structure of the CRL2-ZYG11B holoenzyme alone and in complex with NLRP1 Gly/N-degron peptide shows ZYG11B folds into an LRR domain followed by two ARM repeat domains that mediate CRL2 assembly and substrate recognition; ZYG11B promotes NLRP1 inflammasome activation by recognizing and ubiquitinating the NLRP1 Gly/N-degron revealed after viral protease cleavage. Cryo-EM structure determination, in vitro ubiquitination assays, NLRP1 inflammasome activation assays, blocking experiments bioRxiv (preprint)preprint Medium bio_10.1101_2024.06.24.600508
2020 A truncating mutation in human ZYG11B (p.Glu537*) alters subcellular localization of the truncated protein in HeLa cells; morpholino knockdown of zebrafish ZYG11B homologue disrupts craniofacial cartilage architecture and notochord development; ZYG11B expression regulates the cartilage master regulator SOX6 and is regulated by retinoic acid. Immunofluorescence of mutant ZYG11B in HeLa cells, morpholino knockdown in zebrafish, RT-PCR for SOX6 regulation Molecular genetics & genomic medicine Medium 32738032

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Zyg-11 and cul-2 regulate progression through meiosis II and polarity establishment in C. elegans. Development (Cambridge, England) 108 15215208
2004 CUL-2 and ZYG-11 promote meiotic anaphase II and the proper placement of the anterior-posterior axis in C. elegans. Development (Cambridge, England) 77 15215209
2007 The Caenorhabditis elegans cell-cycle regulator ZYG-11 defines a conserved family of CUL-2 complex components. EMBO reports 47 17304241
2021 Molecular basis for recognition of Gly/N-degrons by CRL2ZYG11B and CRL2ZER1. Molecular cell 35 34214466
2021 ORF10-Cullin-2-ZYG11B complex is not required for SARS-CoV-2 infection. Proceedings of the National Academy of Sciences of the United States of America 31 33827988
1990 Molecular analysis of zyg-11, a maternal-effect gene required for early embryogenesis of Caenorhabditis elegans. Molecular & general genetics : MGG 28 2325632
2020 Functional and genetic analyses of ZYG11B provide evidences for its involvement in OAVS. Molecular genetics & genomic medicine 26 32738032
2022 CRL2ZER1/ZYG11B recognizes small N-terminal residues for degradation. Nature communications 25 36496439
2023 ZYG11B potentiates the antiviral innate immune response by enhancing cGAS-DNA binding and condensation. Cell reports 19 36933219
2023 LncRNA LINC01871 sponging miR-142-3p to modulate ZYG11B promotes the chemoresistance of colorectal cancer cells by inducing autophagy. Anti-cancer drugs 14 36847071
2001 Meiotic human sperm cells express a leucine-rich homologue of Caenorhabditis elegans early embryogenesis gene, Zyg-11. Molecular human reproduction 10 11719588
2025 Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation. Nature communications 8 40082426
2022 Silencing of circular RNA‑ZYG11B exerts a neuroprotective effect against retinal neurodegeneration. International journal of molecular medicine 7 35730627
2022 Structural insights into ORF10 recognition by ZYG11B. Biochemical and biophysical research communications 5 35636250
2025 ZYG11B suppresses multiple enteroviruses by triggering viral VP1 degradation. Journal of virology 3 40135890
2026 Structures of ZYG11B-EloB-EloC-substrate complex reveal mechanisms of CRL2ZYG11B assembly and function. Nature communications 0 41917018