Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release

Yonghong Zhang, Lucas Matt, Tommaso Patriarchi, Zulfiqar A. Malik, Dhrubajyoti Chowdhury, Deborah K. Park, Alessandra Renieri, James B. Ames, Johannes W Hell

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37 Scopus citations

Abstract

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 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 Ca2+-induced dissociation of PSD-95 from the postsynaptic membrane. Synopsis 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 Ca 2+/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 Ca 2+-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. Ca2+ influx promotes Ca 2+/calmodulin binding to the N-terminus of PSD-95, which blocks PSD-95 palmitoylation leading to reduced retention of PSD-95 at synapses.

Original languageEnglish (US)
Pages (from-to)1341-1353
Number of pages13
JournalEMBO Journal
Volume33
Issue number12
DOIs
StatePublished - Jun 17 2014

Keywords

  • calmodulin
  • CDKL5
  • dendritic spines
  • hippocampus
  • PSD-95

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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    Zhang, Y., Matt, L., Patriarchi, T., Malik, Z. A., Chowdhury, D., Park, D. K., Renieri, A., Ames, J. B., & Hell, J. W. (2014). Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release. EMBO Journal, 33(12), 1341-1353. https://doi.org/10.1002/embj.201488126