Premium
Capping of the N ‐terminus of PSD ‐95 by calmodulin triggers its postsynaptic release
Author(s) -
Zhang Yonghong,
Matt Lucas,
Patriarchi Tommaso,
Malik Zulfiqar A,
Chowdhury Dhrubajyoti,
Park Deborah K,
Renieri Alessandra,
Ames James B,
Hell Johannes W
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/embj.201488126
Subject(s) - biology , calmodulin , postsynaptic potential , postsynaptic density , microbiology and biotechnology , biophysics , n terminus , biochemistry , peptide sequence , receptor , enzyme , gene
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 C a 2+ influx via NMDA receptors. Here, we show that C a 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 C 3 and C 5, which is required for postsynaptic PSD ‐95 targeting and the binding of CDKL 5, a kinase important for synapse stability. CaM forms extensive hydrophobic contacts with Y 12 of PSD ‐95. The PSD ‐95 mutant Y 12 E strongly impairs binding to CaM and C a 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 C a 2+ ‐induced dissociation of PSD ‐95 from the postsynaptic membrane.