These authors contributed equally.
Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release
Article first published online: 4 APR 2014
© 2014 The Authors
The EMBO Journal
Volume 33, Issue 12, pages 1341–1353, 17 June 2014
How to Cite
The EMBO Journal (2014) 33: 1341–1353
See also: T Saneyoshi & Y Hayashi (June 2014)
- Issue published online: 24 JUN 2014
- Article first published online: 4 APR 2014
- Manuscript Accepted: 10 MAR 2014
- Manuscript Revised: 7 MAR 2014
- Manuscript Received: 4 FEB 2014
- NIH. Grant Numbers: R01 EY012347, R01 AG017502, R01 NS078792
- American Heart Association Postdoctoral Fellowship. Grant Number: 11POST7020009
- NARSAD Young Investigator. Grant Number: 20748
- Brain & Behavior Research Foundation
- dendritic spines;
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 Ca2+ influx via NMDA receptors. Here, we show that Ca2+/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 Ca2+-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 Ca2+-induced dissociation of PSD-95 from the postsynaptic membrane.
Ca2+ influx promotes Ca2+/calmodulin binding to the N-terminus of PSD-95, which blocks PSD-95 palmitoylation leading to reduced retention of PSD-95 at synapses. This effect will likely decrease postsynaptic glutamate receptor content and thereby synaptic strength.
- Ca2+/calmodulin forms a collapsed structure around the N-terminal helix of PSD-95 that sequesters the palmitoylation sites (Cys3 and Cys5) and a key tyrosine (Tyr12).
- Binding of Ca2+/calmodulin to the N-terminus of PSD-95 decreases its palmitoylation to release PSD-95 from postsynaptic sites
- Binding of Ca2+/calmodulin also displaces the serine/threonine kinase CDKL5 from PSD-95, which otherwise helps augment synaptic strength
- A point mutation of PSD-95 that prevents Ca2+/calmodulin binding turns the Ca2+-induced reduction in PSD-95 at synapses into an increase, uncovering the existence of a second mechanism that augments postsynaptic PSD-95 enrichment upon Ca2+ influx.