ArticleThe Journal of biological chemistry2008
Differential roles of phosphatidylserine, PtdIns(4,5)P2, and PtdIns(3,4,5)P3 in plasma membrane targeting of C2 domains. Molecular dynamics simulation, membrane binding, and cell translocation studies of the PKCalpha C2 domain.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 80 citations in OpenAlex.
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- Binding of CaStructure (London, England : 1993) · 2021Article
- Uncovering Membrane-Bound Models of Coagulation Factors by Combined Experimental and Computational Approaches.Thrombosis and haemostasis · 2021Review
- Molecular Analysis of Membrane Targeting by the C2 Domain of the E3 Ubiquitin Ligase Smurf1.Biomolecules · 2020Article
- The role of phospholipase Cβ on the plasma membrane and in the cytosol: How modular domains enable novel functions.Advances in biological regulation · 2019Article
- Characterization of Lipid-Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation.Chemical reviews · 2019Review
- Polyphosphoinositide-Binding Domains: Insights from Peripheral Membrane and Lipid-Transfer Proteins.Advances in experimental medicine and biology · 2019Review
- Structural Basis of Protein Kinase Cα Regulation by the C-Terminal Tail.Biophysical journal · 2018Article
- Phosphatidylinositol (4, 5)-bisphosphate targets double C2 domain protein B to the plasma membrane.Traffic (Copenhagen, Denmark) · 2017Article
- Investigation of the Effect of Bilayer Composition on PKCα-C2 Domain Docking Using Molecular Dynamics Simulations.The journal of physical chemistry. B · 2017Article
- Notes and tips for improving quality of lipid-protein overlay assays.Analytical biochemistry · 2017Article
- Autocrine Signaling Underlies Fast Repetitive Plasma Membrane Translocation of Conventional and Novel Protein Kinase C Isoforms in β Cells.The Journal of biological chemistry · 2016Article
- Dynamics and Membrane Interactions of Protein Kinase C.Biochemistry · 2015Review
- Insights into the inhibitory mechanism of triazole-based small molecules on phosphatidylinositol-4,5-bisphosphate binding pleckstrin homology domain.Biochemistry and biophysics reports · 2015Article
- Polyphosphoinositide binding domains: Key to inositol lipid biology.Biochimica et biophysica acta · 2015Review
- A novel phosphatidylinositol 4,5-bisphosphate binding domain mediates plasma membrane localization of ExoU and other patatin-like phospholipases.The Journal of biological chemistry · 2015Article
- Simultaneous in situ quantification of two cellular lipid pools using orthogonal fluorescent sensors.Angewandte Chemie (International ed. in English) · 2014Article
- Cellular and molecular interactions of phosphoinositides and peripheral proteins.Chemistry and physics of lipids · 2014Review
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Many cytosolic proteins are recruited to the plasma membrane (PM) during cell signaling and other cellular processes. Recent reports have indicated that phosphatidylserine (PS), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)), and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) that are present in the PM play important roles for their specific PM recruitment. To systematically analyze how these lipids mediate PM targeting of cellular proteins, we performed biophysical, computational, and cell studies of the Ca(2+)-dependent C2 domain of protein kinase Calpha (PKCalpha) that is known to bind PS and phosphoinositides. In vitro membrane binding measurements by surface plasmon resonance analysis show that PKCalpha-C2 nonspecifically binds phosphoinositides, including PtdIns(4,5)P(2) and PtdIns(3,4,5)P(3), but that PS and Ca(2+) binding is prerequisite for productive phosphoinositide binding. PtdIns(4,5)P(2) or PtdIns(3,4,5)P(3) augments the Ca(2+)- and PS-dependent membrane binding of PKCalpha-C2 by slowing its membrane dissociation. Molecular dynamics simulations also support that Ca(2+)-dependent PS binding is essential for membrane interactions of PKCalpha-C2. PtdIns(4,5)P(2) alone cannot drive the membrane attachment of the domain but further stabilizes the Ca(2+)- and PS-dependent membrane binding. When the fluorescence protein-tagged PKCalpha-C2 was expressed in NIH-3T3 cells, mutations of phosphoinositide-binding residues or depletion of PtdIns(4,5)P(2) and/or PtdIns(3,4,5)P(3) from PM did not significantly affect the PM association of the domain but accelerated its dissociation from PM. Also, local synthesis of PtdIns(4,5)P(2) or PtdIns(3,4,5)P(3) at the PM slowed membrane dissociation of PKCalpha-C2. Collectively, these studies show that PtdIns(4,5)P(2) and PtdIns(3,4,5)P(3) augment the Ca(2+)- and PS-dependent membrane binding of PKCalpha-C2 by elongating the membrane residence of the domain but cannot drive the PM recruitment of PKCalpha-C2. These studies also suggest that effective PM recruitment of many cellular proteins may require synergistic actions of PS and phosphoinositides.
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