ArticleThe Journal of biological chemistry2011
Flexible cullins in cullin-RING E3 ligases allosterically regulate ubiquitination.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 52 citations in OpenAlex.
- Cul5: immune cell function and therapeutic potential.Frontiers in immunology · 2026Review
- Discovering Uncharted Binding Pockets on E3 Ligases Leads to the Identification of FBW7 Allosteric Modulators.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Advancements in colorectal cancer research: Unveiling the cellular and molecular mechanisms of neddylation (Review).International journal of oncology · 2024Review
- A heterotypic assembly mechanism regulates CHIP E3 ligase activity.The EMBO journal · 2022Article
- Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity.Nature communications · 2021Article
- Structural Model for Recruitment of RIT1 to the LZTR1 E3 Ligase: Evidences from an Integrated Computational Approach.Journal of chemical information and modeling · 2021Article
- Characterization of an A3G-VifMolecular & cellular proteomics : MCP · 2021Article
- Structure and dynamics of the ASB9 CUL-RING E3 Ligase.Nature communications · 2020Article
- The functions and properties of cullin-5, a potential therapeutic target for cancers.American journal of translational research · 2020Review
- E3 ligase Herc4 regulates Hedgehog signalling through promoting Smoothened degradation.Journal of molecular cell biology · 2019Article
- Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery.RSC advances · 2019Review
- Folding cooperativity and allosteric function in the tandem-repeat protein class.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2018Review
- Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex.Structure (London, England : 1993) · 2017Article
- Cullin neddylation may allosterically tune polyubiquitin chain length and topology.The Biochemical journal · 2017Article
- Induced protein degradation: an emerging drug discovery paradigm.Nature reviews. Drug discovery · 2017Review
- Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System.The Journal of biological chemistry · 2016Review
- The role of cullin 5-containing ubiquitin ligases.Cell division · 2016Review
- Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators.European journal of medicinal chemistry · 2015Article
- Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia.EMBO molecular medicine · 2015Article
- Stability of HIB-Cul3 E3 ligase adaptor HIB Is Regulated by Self-degradation and Availability of Its Substrates.Scientific reports · 2015Article
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
Abstract
How do the cullins, with conserved structures, accommodate substrate-binding proteins with distinct shapes and sizes? Cullin-RING E3 ubiquitin ligases facilitate ubiquitin transfer from E2 to the substrate, tagging the substrate for degradation. They contain substrate-binding, adaptor, cullin, and Rbx proteins. Previously, we showed that substrate-binding and Rbx proteins are flexible. This allows shortening of the E2-substrate distance for initiation of ubiquitination or increasing the distance to accommodate the polyubiquitin chain. However, the role of the cullin remained unclear. Is cullin a rigid scaffold, or is it flexible and actively assists in the ubiquitin transfer reaction? Why are there different cullins, and how do these cullins specifically facilitate ubiquitination for different substrates? To answer these questions, we performed structural analysis and molecular dynamics simulations based on Cul1, Cul4A, and Cul5 crystal structures. Our results show that these three cullins are not rigid scaffolds but are flexible with conserved hinges in the N-terminal domain. However, the degrees of flexibilities are distinct among the different cullins. Of interest, Cul1 flexibility can also be changed by deletion of the long loop (which is absent in Cul4A) in the N-terminal domain, suggesting that the loop may have an allosteric functional role. In all three cases, these conformational changes increase the E2-substrate distance to a specific range to facilitate polyubiquitination, suggesting that rather than being inert scaffold proteins, cullins allosterically regulate ubiquitination.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.