ArticleProceedings of the National Academy of Sciences of the United States of America2013
Insights into the regulation of the human COP9 signalosome catalytic subunit, CSN5/Jab1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 107 citations in OpenAlex.
- Mechanism of K63-linked polyubiquitin recognition and cleavage by the BRCA1-A complex.Nature communications · 2026Article
- Protein neddylation as a therapeutic target: challenges and opportunities.The Journal of clinical investigation · 2026Review
- Neddylation: from regulatory mechanisms to clinical implications in cancer.Journal of advanced research · 2026Review
- COP9 signalosome deneddylation activity is required for proliferation but not dedifferentiation of vascular smooth muscle cells in neointimal hyperplasia.American journal of physiology. Heart and circulatory physiology · 2026Article
- JAB1/CRL4B complex represses PPARG/ACSL5 expression to promote breast tumorigenesis.Cell death and differentiation · 2026Article
- Structural basis of CSN-mediated SCF deneddylation.Nature communications · 2026Article
- Jab1 regulates HRR mRNA stability to modulate PARP inhibitor sensitivity in triple-negative breast cancer.Molecular cancer · 2025Article
- Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells.iScience · 2024Article
- Advancing Cancer Immunotherapy through Engineering New PD-L1 Degraders: A Comprehensive Study from Small Molecules to PD-L1-Specific Peptide-Drug Conjugates.Journal of medicinal chemistry · 2024Article
- Altered assembly paths mitigate interference among paralogous complexes.Nature communications · 2024Article
- COP9 signalosome component CSN-5 stabilizes PUF proteins FBF-1 and FBF-2 in Caenorhabditis elegans germline stem and progenitor cells.Genetics · 2024Article
- Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024Review
- USP48 and A20 synergistically promote cell survival in Helicobacter pylori infection.Cellular and molecular life sciences : CMLS · 2022Article
- Structural and Functional Basis of JAMM Deubiquitinating Enzymes in Disease.Biomolecules · 2022Review
- The Cellular and Developmental Roles of Cullins, Neddylation, and the COP9 Signalosome inFrontiers in physiology · 2022Review
- SENP1 promotes triple-negative breast cancer invasion and metastasis via enhancing CSN5 transcription mediated by GATA1 deSUMOylation.International journal of biological sciences · 2022Article
- Machine Learning-Enabled Pipeline for Large-Scale Virtual Drug Screening.Journal of chemical information and modeling · 2021Article
- Identification of a seven-long non-coding RNA signature associated with Jab1/CSN5 in predicting hepatocellular carcinoma.Cell death discovery · 2021Article
- Cullin-RING Ubiquitin Ligase Regulatory Circuits: A Quarter Century Beyond the F-Box Hypothesis.Annual review of biochemistry · 2021Review
- Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development inBiomolecules · 2021Article
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Authors and funding
10 authors at 7 institutions in 2 countries.
Funding
Abstract
The COP9 (Constitutive photomorphogenesis 9) signalosome (CSN), a large multiprotein complex that resembles the 19S lid of the 26S proteasome, plays a central role in the regulation of the E3-cullin RING ubiquitin ligases (CRLs). The catalytic activity of the CSN complex, carried by subunit 5 (CSN5/Jab1), resides in the deneddylation of the CRLs that is the hydrolysis of the cullin-neural precursor cell expressed developmentally downregulated gene 8 (Nedd8)isopeptide bond. Whereas CSN-dependent CSN5 displays isopeptidase activity, it is intrinsically inactive in other physiologically relevant forms. Here we analyze the crystal structure of CSN5 in its catalytically inactive form to illuminate the molecular basis for its activation state. We show that CSN5 presents a catalytic domain that brings essential elements to understand its activity control. Although the CSN5 active site is catalytically competent and compatible with di-isopeptide binding, the Ins-1 segment obstructs access to its substrate-binding site, and structural rearrangements are necessary for the Nedd8-binding pocket formation. Detailed study of CSN5 by molecular dynamics unveils signs of flexibility and plasticity of the Ins-1 segment. These analyses led to the identification of a molecular trigger implicated in the active/inactive switch that is sufficient to impose on CSN5 an active isopeptidase state. We show that a single mutation in the Ins-1 segment restores biologically relevant deneddylase activity. This study presents detailed insights into CSN5 regulation. Additionally, a dynamic monomer-dimer equilibrium exists both in vitro and in vivo and may be functionally relevant.
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