Gene interactions and pathways from curated databases and text-mining
EMBO J 2008, PMID: 18273061

Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.

Ng, Cherlyn; Jackson, Rebecca A; Buschdorf, Jan P; Sun, Qingxiang; Guy, Graeme R; Sivaraman, J

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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Text Mining Data

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Manually curated Databases

  • IRef Biogrid Interaction: CBL — SPRY2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CBL — SPRY2 (association, x-ray crystallography)
  • IRef Biogrid Interaction: CBL — GRB2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CBL — MET (association, x-ray crystallography)
  • IRef Biogrid Interaction: CBL — MET (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CBL — EGFR (association, x-ray crystallography)
  • IRef Biogrid Interaction: CBL — EGFR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: SH2B2 — CBL (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CBL — SPRY4 (physical association, affinity chromatography technology)
  • IRef Hprd Interaction: SYK — CBL (in vitro)
  • IRef Hprd Interaction: SYK — CBL (in vivo)
  • IRef Hprd Interaction: CBL — SPRY2 (in vivo)
  • IRef Hprd Interaction: CBL — SPRY2 (in vitro)
  • IRef Hprd Interaction: CBL — SPRY2 (two hybrid)
  • IRef Hprd Interaction: CBL — GRB2 (in vitro)
  • IRef Hprd Interaction: CBL — GRB2 (in vivo)
  • IRef Hprd Interaction: CBL — MET (in vitro)
  • IRef Hprd Interaction: CBL — MET (two hybrid)
  • IRef Hprd Interaction: CBL — MET (in vivo)
  • IRef Hprd Interaction: CBL — EGFR (in vivo)
  • IRef Hprd Interaction: CBL — EGFR (in vitro)
  • IRef Hprd Interaction: SRC — CBL (in vivo)
  • IRef Hprd Interaction: SRC — CBL (in vitro)
  • IRef Hprd Interaction: FNBP1 — CBL (in vitro)
  • IRef Hprd Interaction: FNBP1 — CBL (in vivo)
  • IRef Hprd Interaction: SH2B2 — CBL (in vivo)
  • IRef Hprd Interaction: SH2B2 — CBL (in vitro)
  • IRef Intact Interaction: SYK — CBL (direct interaction, isothermal titration calorimetry)
  • IRef Intact Interaction: SYK — CBL (direct interaction, x-ray crystallography)
  • IRef Intact Interaction: CBL — SPRY2 (direct interaction, x-ray crystallography)
  • IRef Intact Interaction: CBL — SPRY2 (direct interaction, isothermal titration calorimetry)
  • IRef Intact Interaction: CBL — SPRY2 (physical association, anti tag coimmunoprecipitation)
  • IRef Intact Interaction: GRB2 — CBL (physical association, anti bait coimmunoprecipitation)
  • IRef Intact Interaction: CBL — MST1R (direct interaction, isothermal titration calorimetry)
  • IRef Intact Interaction: CBL — MET (direct interaction, isothermal titration calorimetry)
  • IRef Intact Interaction: CBL — MET (physical association, anti bait coimmunoprecipitation)
  • IRef Intact Interaction: CBL — MET (direct interaction, x-ray crystallography)
  • IRef Intact Interaction: CBL — EGFR (physical association, anti bait coimmunoprecipitation)
  • IRef Intact Interaction: CBL — EGFR (direct interaction, x-ray crystallography)
  • IRef Intact Interaction: CBL — EGFR (direct interaction, isothermal titration calorimetry)
  • IRef Intact Interaction: SRC — CBL (direct interaction, isothermal titration calorimetry)
  • IRef Intact Interaction: FLT1 — CBL (direct interaction, isothermal titration calorimetry)
  • IRef Intact Interaction: SH2B2 — CBL (direct interaction, isothermal titration calorimetry)
  • IRef Intact Interaction: SH2B2 — CBL (physical association, anti tag coimmunoprecipitation)
  • IRef Intact Interaction: SPRY4 — CBL (physical association, anti tag coimmunoprecipitation)
  • IRef Intact Interaction: SPRY4 — CBL (direct interaction, x-ray crystallography)
  • IRef Intact Interaction: SPRY4 — CBL (direct interaction, isothermal titration calorimetry)
In total, 11 gene pairs are associated to this article in curated databases