ArticleBiochemistry2014
The structure and specificity of the type III secretion system effector NleC suggest a DNA mimicry mechanism of substrate recognition.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 33 citations in OpenAlex.
- Evolution of N-terminal mechanical lability as a determinant for Type III secretion.Protein science : a publication of the Protein Society · 2026Article
- A Type III secretion system effector evolved to be mechanically labile and initiate unfolding from the N-terminus.bioRxiv : the preprint server for biology · 2026Article
- AIP56, an AB toxin secreted byFrontiers in immunology · 2024Article
- Unconventional structure and mechanisms for membrane interaction and translocation of the NF-κB-targeting toxin AIP56.Nature communications · 2023Article
- How Do Biomolecules Cross the Cell Membrane?Accounts of chemical research · 2022Article
- Bacterial Toxins Escape the Endosome by Inducing Vesicle Budding and Collapse.ACS chemical biology · 2021Article
- Host manipulation by bacterial type III and type IV secretion system effector proteases.Cellular microbiology · 2021Review
- α-Helices in the Type III Secretion Effectors: A Prevalent Feature with Versatile Roles.International journal of molecular sciences · 2021Review
- The T3SS Effector Protease NleC Is Active withinPathogens (Basel, Switzerland) · 2021Article
- Interesting Biochemistries in the Structure and Function of Bacterial Effectors.Frontiers in cellular and infection microbiology · 2021Review
- Measuring Effector-Mediated Modulation of Inflammatory Responses to Infection with Enteropathogenic and Shiga Toxin-Producing E. coli.Methods in molecular biology (Clifton, N.J.) · 2021Article
- How a DNA mimic catches and cleaves NF-κB.The Journal of biological chemistry · 2018Article
- Structure-function analyses of the bacterial zinc metalloprotease effector protein GtgA uncover key residues required for deactivating NF-κB.The Journal of biological chemistry · 2018Article
- Cooperative Immune Suppression by Escherichia coli and Shigella Effector Proteins.Infection and immunity · 2018Review
- T3SS-Independent Uptake of the Short-Trip Toxin-Related Recombinant NleC Effector of EnteropathogenicFrontiers in cellular and infection microbiology · 2017Article
- Interference with nuclear factor kappaB signaling pathway by pathogen-encoded proteases: global and selective inhibition.Molecular microbiology · 2016Review
- Metalloprotease NleC suppresses host NF-κB/inflammatory responses by cleaving p65 and interfering with the p65/RPS3 interaction.PLoS pathogens · 2015Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Many pathogenic bacteria utilize the type III secretion system (T3SS) to translocate effector proteins directly into host cells, facilitating colonization. In enterohemmorhagic Escherichia coli (EHEC), a subset of T3SS effectors is essential for suppression of the inflammatory response in hosts, including humans. Identified as a zinc protease that cleaves NF-κB transcription factors, NleC is one such effector. Here, we investigate NleC substrate specificity, showing that four residues around the cleavage site in the DNA-binding loop of the NF-κB subunit RelA strongly influence the cleavage rate. Class I NF-κB subunit p50 is cleaved at a reduced rate consistent with conservation of only three of these four residues. However, peptides containing 10 residues on each side of the scissile bond were not efficiently cleaved by NleC, indicating that elements distal from the cleavage site are also important for substrate recognition. We present the crystal structure of NleC and show that it mimics DNA structurally and electrostatically. Consistent with this model, mutation of phosphate-mimicking residues in NleC reduces the level of RelA cleavage. We propose that global recognition of NF-κB subunits by DNA mimicry combined with a high sequence selectivity for the cleavage site results in exquisite NleC substrate specificity. The structure also shows that despite undetectable similarity of its sequence to those of other Zn(2+) proteases beyond its conserved HExxH Zn(2+)-binding motif, NleC is a member of the Zincin protease superfamily, albeit divergent from its structural homologues. In particular, NleC displays a modified Ψ-loop motif that may be important for folding and refolding requirements implicit in T3SS translocation.
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