Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release
Copyright policy )Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release
Postsynaptic density protein-95 (PSD-95) is a central element of the postsynaptic architecture of glutamatergic synapses. PSD-95 mediates postsynaptic localization of AMPA receptors and NMDA receptors and plays an important role in synaptic plasticity. PSD-95 is released from postsynaptic membranes in response to Ca(2+) influx via NMDA receptors. Here, we show that Ca(2+)/calmodulin (CaM) binds at the N-terminus of PSD-95. Our NMR structure reveals that both lobes of CaM collapse onto a helical structure of PSD-95 formed at its N-terminus (residues 1-16). This N-terminal capping of PSD-95 by CaM blocks palmitoylation of C3 and C5, which is required for postsynaptic PSD-95 targeting and the binding of CDKL5, a kinase important for synapse stability. CaM forms extensive hydrophobic contacts with Y12 of PSD-95. The PSD-95 mutant Y12E strongly impairs binding to CaM and Ca(2+)-induced release of PSD-95 from the postsynaptic membrane in dendritic spines. Our data indicate that CaM binding to PSD-95 serves to block palmitoylation of PSD-95, which in turn promotes Ca(2+)-induced dissociation of PSD-95 from the postsynaptic membrane.
- University of California, San Francisco United States
- University of Siena Italy
- University of California, Davis United States
Magnetic Resonance Spectroscopy (mesh), calmodulin, Magnetic Resonance Spectroscopy, hippocampus, Protein Conformation, Histological Techniques (mesh), calmodulin; CDKL5; dendritic spines; hippocampus; PSD-95, 11 Medical and Health Sciences (for), Medical and Health Sciences, Hippocampus, Immunoprecipitation (mesh), Post-Synaptic Density (mesh), Models, 31 Biological sciences (for-2020), Animals (mesh), 32 Biomedical and Clinical Sciences (for-2020), Neurosciences (rcdc), Cells, Cultured, Developmental Biology (science-metrix), Neurons, Membrane Proteins (mesh), Cultured, dendritic spine, Histological Techniques, Intracellular Signaling Peptides and Proteins, Biological Sciences, 06 Biological Sciences (for), Rats (mesh), CDKL5, Neurological, PSD‐95, Cultured (mesh), Disks Large Homolog 4 Protein, 570, 1.1 Normal biological development and functioning, Cells, Intracellular Signaling Peptides and Proteins (mesh), Immunoblotting, Models, Neurological, 08 Information and Computing Sciences (for), Fluorescence, Calmodulin, Information and Computing Sciences, 616, Immunoblotting (mesh), Animals, Immunoprecipitation, PSD-95, 1.1 Normal biological development and functioning (hrcs-rac), 31 Biological Sciences (for-2020), Neurons (mesh), Protein Conformation (mesh), Biomedical and Clinical Sciences, hippocampu, Fluorescence (mesh), Neurosciences, Membrane Proteins, Post-Synaptic Density, dendritic spines, 3101 Biochemistry and Cell Biology (for-2020), Rats, Calmodulin (mesh), 32 Biomedical and clinical sciences (for-2020), Biochemistry and Cell Biology, Disks Large Homolog 4 Protein (mesh), Neurological (mesh), Hippocampus (mesh), Developmental Biology
Magnetic Resonance Spectroscopy (mesh), calmodulin, Magnetic Resonance Spectroscopy, hippocampus, Protein Conformation, Histological Techniques (mesh), calmodulin; CDKL5; dendritic spines; hippocampus; PSD-95, 11 Medical and Health Sciences (for), Medical and Health Sciences, Hippocampus, Immunoprecipitation (mesh), Post-Synaptic Density (mesh), Models, 31 Biological sciences (for-2020), Animals (mesh), 32 Biomedical and Clinical Sciences (for-2020), Neurosciences (rcdc), Cells, Cultured, Developmental Biology (science-metrix), Neurons, Membrane Proteins (mesh), Cultured, dendritic spine, Histological Techniques, Intracellular Signaling Peptides and Proteins, Biological Sciences, 06 Biological Sciences (for), Rats (mesh), CDKL5, Neurological, PSD‐95, Cultured (mesh), Disks Large Homolog 4 Protein, 570, 1.1 Normal biological development and functioning, Cells, Intracellular Signaling Peptides and Proteins (mesh), Immunoblotting, Models, Neurological, 08 Information and Computing Sciences (for), Fluorescence, Calmodulin, Information and Computing Sciences, 616, Immunoblotting (mesh), Animals, Immunoprecipitation, PSD-95, 1.1 Normal biological development and functioning (hrcs-rac), 31 Biological Sciences (for-2020), Neurons (mesh), Protein Conformation (mesh), Biomedical and Clinical Sciences, hippocampu, Fluorescence (mesh), Neurosciences, Membrane Proteins, Post-Synaptic Density, dendritic spines, 3101 Biochemistry and Cell Biology (for-2020), Rats, Calmodulin (mesh), 32 Biomedical and clinical sciences (for-2020), Biochemistry and Cell Biology, Disks Large Homolog 4 Protein (mesh), Neurological (mesh), Hippocampus (mesh), Developmental Biology
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