ArticleScientific reports2017
Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Domain-dependent uncoupling of the co-chaperone and E3 ubiquitin ligase CHIP underlies heterogeneity in spinocerebellar ataxia 48.The Journal of biological chemistry · 2026Article
- Photocross-linking activity-based probes to capture the dynamics of ubiquitin RING E3 ligase interactions.The Biochemical journal · 2026Article
- Fine-Tuning Protein Fate: Mechanisms of E1, E2, and E3 Enzymes and Deubiquitinases in Cell Signaling.International journal of molecular sciences · 2026Review
- Ubiquitin E3 Ligases and p53 in Doxorubicin-Induced Cardiotoxicity.International journal of molecular sciences · 2025Review
- Molecular features defining the efficiency of bioPROTACs.Communications biology · 2025Article
- Chaperone-assisted E3 ligase-engineered mesenchymal stem cells target hyperglycemia-induced p53 for ubiquitination and proteasomal degradation ameliorates self-renewal.Biological research · 2025Article
- A heterotypic assembly mechanism regulates CHIP E3 ligase activity.The EMBO journal · 2022Article
- E3 ligase activity of Carboxyl terminus of Hsc70 interacting protein (CHIP) in Wharton's jelly derived mesenchymal stem cells improves their persistence under hyperglycemic stress and promotes the prophylactic effects against diabetic cardiac damages.Bioengineering & translational medicine · 2021Article
- S-nitrosothiols signaling in cystic fibrosis airways.Journal of biosciences · 2021Review
- C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside.Current neuropharmacology · 2021Review
- Disulfide Reduction Allosterically Destabilizes the β-Ladder Subdomain Assembly within the NS1 Dimer of ZIKV.Biophysical journal · 2020Article
- Ubiquitination of disease-causing CFTR variants in a microsome-based assay.Analytical biochemistry · 2020Article
- Article
- The cochaperone CHIP marks Hsp70- and Hsp90-bound substrates for degradation through a very flexible mechanism.Scientific reports · 2019Article
- Neuronal Preconditioning Requires the Mitophagic Activity of C-terminus of HSC70-Interacting Protein.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
C-terminus of Hsc/p70-Interacting Protein (CHIP) is a homodimeric E3 ubiquitin ligase. Each CHIP monomer consists of a tetratricopeptide-repeat (TPR), helix-turn-helix (HH), and U-box domain. In contrast to nearly all homodimeric proteins, CHIP is asymmetric. To uncover the origins of asymmetry, we performed molecular dynamics simulations of dimer assembly. We determined that a CHIP monomer is most stable when the HH domain has an extended helix that supports intra-monomer TPR-U-box interaction, blocking the E2-binding surface of the U-box. We also discovered that monomers first dimerize symmetrically through their HH domains, which then triggers U-box dimerization. This brings the extended helices into close proximity, including a repulsive stretch of positively charged residues. Unable to smoothly unwind, this conflict bends the helices until the helix of one protomer breaks to relieve the repulsion. The abrupt snapping of the helix forces the C-terminal residues of the other protomer to disrupt that protomer's TPR-U-box tight binding interface, swiftly exposing and activating one of the E2 binding sites. Mutagenesis and biochemical experiments confirm that C-terminal residues are necessary both to maintain CHIP stability and function. This novel mechanism indicates how a ubiquitin ligase maintains an inactive monomeric form that rapidly activates only after asymmetric assembly.
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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.