ArticleThe EMBO journal2008
Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.
Article in The EMBO journal, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed.
- A c-Cbl/Cbl-b antagonist inhibits EGFR ubiquitylation and sustains EGFR phosphorylation to enhance corneal re-epithelialization.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Proteomics- and BRET- screens identify SPRY2 as a Ras effector that impacts its membrane organization.iScience · 2025Article
- Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Proteolysis-targeting influenza vaccine strains induce broad-spectrum immunity and in vivo protection.Nature microbiology · 2025Article
- Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.The Journal of clinical investigation · 2024Article
- DEGRONOPEDIA: a web server for proteome-wide inspection of degrons.Nucleic acids research · 2024Article
- An innate pathogen sensing strategy involving ubiquitination of bacterial surface proteins.Science advances · 2023Article
- Engineering SH2 Domains with Tailored Specificities and Affinities.Methods in molecular biology (Clifton, N.J.) · 2023Article
- E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK-CBL-CIN85 axis.Oncogene · 2021Article
- Sleuthing biochemical evidence to elucidate unassigned electron density in a CBL-SLAP2 crystal complex.Acta crystallographica. Section F, Structural biology communications · 2021Article
- Structural insights into a HECT-type E3 ligase AREL1 and its ubiquitination activitiesThe Journal of biological chemistry · 2019Article
- Feedback regulation of RTK signaling in development.Developmental biology · 2019Review
- Phosphorylation control of the ubiquitin ligase Cbl is conserved in choanoflagellates.Protein science : a publication of the Protein Society · 2018Article
- Casitas B-lineage lymphoma linker helix mutations found in myeloproliferative neoplasms affect conformation.BMC biology · 2016Article
- Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System.The Journal of biological chemistry · 2016Review
- The Insect Peptide CopA3 Increases Colonic Epithelial Cell Proliferation and Mucosal Barrier Function to Prevent Inflammatory Responses in the Gut.The Journal of biological chemistry · 2016Article
- Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system.Nature communications · 2016Article
- Structural basis for the indispensable role of a unique zinc finger motif in LNX2 ubiquitination.Oncotarget · 2015Article
- Structural determinants of nuclear export signal orientation in binding to exportin CRM1.eLife · 2015Article
- The developing story of Sprouty and cancer.Cancer metastasis reviews · 2014Review
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The c-Cbl tyrosine kinase binding domain (Cbl-TKB), essentially an 'embedded' SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate-binding affinity, we compared crystal structures of the Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors and validated the binding with point-mutational analyses using full-length proteins. An obligatory, intrapeptidyl H-bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orients the peptide into a positively charged pocket on c-Cbl. Surprisingly, c-Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H-bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c-Cbl; this may enable the selective sequestration of c-Cbl from other target proteins.
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