ArticleThe Journal of biological chemistry2012
Molecular basis for failure of "atypical" C1 domain of Vav1 to bind diacylglycerol/phorbol ester.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 17 citations in OpenAlex.
- Novel DAG-Lactone-Based Vav1 Inhibitors Show Anti-proliferative Activity in Pancreatic Cancer Models.ChemMedChem · 2025Article
- Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway.Pharmaceuticals (Basel, Switzerland) · 2020Review
- Structural determinants of phorbol ester binding activity of the C1a and C1b domains of protein kinase C theta.Biochimica et biophysica acta. Biomembranes · 2018Article
- The C1 domain of Vav3, a novel potential therapeutic target.Cellular signalling · 2017Article
- Curcumin Inhibits Protein Kinase Cα Activity by Binding to Its C1 Domain.Biochemistry · 2016Article
- Structural Basis for the Failure of the C1 Domain of Ras Guanine Nucleotide Releasing Protein 2 (RasGRP2) to Bind Phorbol Ester with High Affinity.The Journal of biological chemistry · 2016Article
- Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP.Bioorganic & medicinal chemistry · 2014Article
- Charge density influences C1 domain ligand affinity and membrane interactions.Chembiochem : a European journal of chemical biology · 2014Article
- Diacylglycerol lactones targeting the structural features that distinguish the atypical C1 domains of protein kinase C ζ and ι from typical C1 domains.Journal of medicinal chemistry · 2014Article
- Vav family exchange factors: an integrated regulatory and functional view.Small GTPases · 2014Review
- Identification of the activator-binding residues in the second cysteine-rich regulatory domain of protein kinase Cθ (PKCθ).The Biochemical journal · 2013Article
- Bruton's Tyrosine Kinase (BTK) and Vav1 contribute to Dectin1-dependent phagocytosis of Candida albicans in macrophages.PLoS pathogens · 2013Article
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
Abstract
C1 domains, the recognition motif of the second messenger diacylglycerol and of the phorbol esters, are classified as typical (ligand-responsive) or atypical (not ligand-responsive). The C1 domain of Vav1, a guanine nucleotide exchange factor, plays a critical role in regulation of Vav activity through stabilization of the Dbl homology domain, which is responsible for exchange activity of Vav. Although the C1 domain of Vav1 is classified as atypical, it retains a binding pocket geometry homologous to that of the typical C1 domains of PKCs. This study clarifies the basis for its failure to bind ligands. Substituting Vav1-specific residues into the C1b domain of PKCδ, we identified five crucial residues (Glu(9), Glu(10), Thr(11), Thr(24), and Tyr(26)) along the rim of the binding cleft that weaken binding potency in a cumulative fashion. Reciprocally, replacing these incompatible residues in the Vav1 C1 domain with the corresponding residues from PKCδ C1b (δC1b) conferred high potency for phorbol ester binding. Computer modeling predicts that these unique residues in Vav1 increase the hydrophilicity of the rim of the binding pocket, impairing membrane association and thereby preventing formation of the ternary C1-ligand-membrane binding complex. The initial design of diacylglycerol-lactones to exploit these Vav1 unique residues showed enhanced selectivity for C1 domains incorporating these residues, suggesting a strategy for the development of ligands targeting Vav1.
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