ArticleThe Biochemical journal2013
Identification of the activator-binding residues in the second cysteine-rich regulatory domain of protein kinase Cθ (PKCθ).
Article in The Biochemical journal, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- A membrane-sensing mechanism links lipid metabolism to protein degradation at the nuclear envelope.The Journal of cell biology · 2023Article
- Comparison of the ligand binding site of C1 domains: a molecular dynamics simulation study of the C1 domain-phorbol 13-acetate-membrane system.Journal of biomolecular structure & dynamics · 2023Article
- Structural anatomy of Protein Kinase C C1 domain interactions with diacylglycerol and other agonists.Nature communications · 2022Article
- Probing the Diacylglycerol Binding Site of Presynaptic Munc13-1.Biochemistry · 2021Article
- Structural insights into C1-ligand interactions: Filling the gaps by in silico methods.Advances in biological regulation · 2021Review
- Effect of ethanol on Munc13-1 C1 in Membrane: A Molecular Dynamics Simulation Study.Alcoholism, clinical and experimental research · 2020Article
- Spinal activation of protein kinase C elicits phrenic motor facilitation.Respiratory physiology & neurobiology · 2018Article
- Structural determinants of phorbol ester binding activity of the C1a and C1b domains of protein kinase C theta.Biochimica et biophysica acta. Biomembranes · 2018Article
- Critical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation.Biochemistry · 2018Article
- REDOR NMR Reveals Multiple Conformers for a Protein Kinase C Ligand in a Membrane Environment.ACS central science · 2018Article
- Exploring the influence of indololactone structure on selectivity for binding to the C1 domains of PKCα, PKCε, and RasGRP.Bioorganic & medicinal chemistry · 2017Article
- Curcumin Inhibits Protein Kinase Cα Activity by Binding to Its C1 Domain.Biochemistry · 2016Article
- Dynamics and Membrane Interactions of Protein Kinase C.Biochemistry · 2015Review
- Phrenic long-term facilitation requires PKCθ activity within phrenic motor neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Toward a biorelevant structure of protein kinase C bound modulators: design, synthesis, and evaluation of labeled bryostatin analogues for analysis with rotational echo double resonance NMR spectroscopy.Journal of the American Chemical Society · 2015Article
- Improved protein kinase C affinity through final step diversification of a simplified salicylate-derived bryostatin analog scaffold.Organic letters · 2014Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
PKC (protein kinase C) θ is predominantly expressed in T-cells and is critically involved in immunity. Design of PKCθ-selective molecules to manage autoimmune disorders by targeting its activator-binding C1 domain requires the knowledge of its structure and the activator-binding residues. The C1 domain consists of twin C1 domains, C1A and C1B, of which C1B plays a critical role in the membrane translocation and activation of PKCθ. In the present study we determined the crystal structure of PKCθC1B to 1.63 Å (1 Å=0.1 nm) resolution, which showed that Trp(253) at the rim of the activator-binding pocket was orientated towards the membrane, whereas in PKCδC1B the homologous tryptophan residue was orientated away from the membrane. This particular orientation of Trp(253) affects the size of the activator-binding pocket and the membrane affinity. To further probe the structural constraints on activator-binding, five residues lining the activator-binding site were mutated (Y239A, T243A, W253G, L255G and Q258G) and the binding affinities of the PKCθC1B mutants were measured. These mutants showed reduced binding affinities for phorbol ester [PDBu (phorbol 12,13-dibutyrate)] and diacylglycerol [DOG (sn-1,2-dioctanoylglycerol), SAG (sn-1-stearoyl 2-arachidonyl glycerol)]. All five full-length PKCθ mutants exhibited reduced phorbol-ester-induced membrane translocation compared with the wild-type. These results provide insights into the PKCθ activator-binding domain, which will aid in future design of PKCθ-selective molecules.
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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.