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.
Department of Chemistry, University of California, Davis, CA, USA.
Yonghong
Y
Zhang
Department of Pharmacology, University of California, Davis, CA, USA.
Lucas
L
Matt
Department of Pharmacology, University of California, Davis, CA, USA Department of Medical Genetics, University of Siena, Siena, Italy.
Tommaso
T
Patriarchi
Department of Pharmacology, University of California, Davis, CA, USA.
Zulfiqar A
ZA
Malik
Department of Pharmacology, University of California, Davis, CA, USA.
Dhrubajyoti
D
Chowdhury
Department of Pharmacology, University of California, Davis, CA, USA.
Deborah K
DK
Park
Department of Medical Genetics, University of Siena, Siena, Italy.
Alessandra
A
Renieri
Department of Chemistry, University of California, Davis, CA, USA jbames@ucdavis.edu jwhell@ucdavis.edu.
James B
JB
Ames
Department of Pharmacology, University of California, Davis, CA, USA jbames@ucdavis.edu jwhell@ucdavis.edu.
Johannes W
JW
Hell
D000818:Animals; D002147:Calmodulin / Q000378:metabolism*; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D005453:Fluorescence; D006624:Hippocampus / Q000166:cytology*; D006652:Histological Techniques; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000378:metabolism*; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism*; D057907:Post-Synaptic Density / Q000378:metabolism*; D011487:Protein Conformation; D051381:Rats
D002147:Calmodulin; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins
CDKL5; PSD‐95; calmodulin; dendritic spines; hippocampus