@article{96e74c64f0bf4182bb461e27541ca8af,
title = "Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses",
abstract = "The post-synaptic density protein 95 (PSD-95) plays a central role in excitatory synapse development and synaptic plasticity. Phosphorylation of the N-terminus of PSD-95 at threonine 19 (T19) and serine 25 (S25) decreases PSD-95 stability at synapses; however, a molecular mechanism linking PSD-95 phosphorylation to altered synaptic stability is lacking. Here, we show that phosphorylation of T19/S25 recruits the phosphorylation-dependent peptidyl-prolyl cis–trans isomerase (Pin1) and reduces the palmitoylation of Cysteine 3 and Cysteine 5 in PSD-95. This reduction in PSD-95 palmitoylation accounts for the observed loss in the number of dendritic PSD-95 clusters, the increased AMPAR mobility, and the decreased number of functional excitatory synapses. We find the effects of Pin1 overexpression were all rescued by manipulations aimed at increasing the levels of PSD-95 palmitoylation. Therefore, Pin1 is a key signaling molecule that regulates the stability of excitatory synapses and may participate in the destabilization of PSD-95 following the induction of synaptic plasticity.",
keywords = "Pin1, cis–trans isomerization, excitatory synaptic transmission, palmitoylation, post-synaptic density protein 95, proline-directed phosphorylation",
author = "Delgado, {Jary Y.} and Duncan Nall and Selvin, {Paul R.}",
note = "Funding Information: We thank Dr. Paul F. Workey for carefully evaluating the ideas presented in this work. Special thanks to Elena Solomaha for technical assistance with the SPR experiments. Mark Karver performed the synthesis of the peptides at the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University. To The University of Chicago Confocal Microscopy services and Bordeaux Imaging Facilities in particular to Vytas Bindokas. To Drs. Daniel Choquet, William N. Green, Xiaoxi Zhuang for sharing equipment and financial support, especially to William N. Green for financial support via the DA035430 grant. To Dr. Gopal Thinakaran for reagents. To Meera Patel and Jason Thome for carefully editing earlier versions of the manuscript. Funding. AMPAzeta IIF Marie Curie Fellowship and NIH Grant NS103159 to JD, NIH NS100019 and NSF PHY-1430124 to PS, and T32 NS0072419?28 to Eve Marder. Funding Information: AMPAzeta IIF Marie Curie Fellowship and NIH Grant NS103159 to JD, NIH NS100019 and NSF PHY-1430124 to PS, and T32 NS0072419–28 to Eve Marder. Funding Information: We thank Dr. Paul F. Workey for carefully evaluating the ideas presented in this work. Special thanks to Elena Solomaha for technical assistance with the SPR experiments. Mark Karver performed the synthesis of the peptides at the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University. To The University of Chicago Confocal Microscopy services and Bordeaux Imaging Facilities in particular to Vytas Bindokas. To Drs. Daniel Choquet, William N. Green, Xiaoxi Zhuang for sharing equipment and financial support, especially to William N. Green for financial support via the DA035430 grant. To Dr. Gopal Thinakaran for reagents. To Meera Patel and Jason Thome for carefully editing earlier versions of the manuscript. Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2020 Delgado, Nall and Selvin.",
year = "2020",
month = mar,
day = "13",
doi = "10.3389/fnmol.2020.00010",
language = "English (US)",
volume = "13",
journal = "Frontiers in Molecular Neuroscience",
issn = "1662-5099",
publisher = "Frontiers Research Foundation",
}