Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses
Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses
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DOI：
10.3389/fnmol.2020.00010
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发表时间：
2020-03-13
影响因子：
4.8
通讯作者：
Selvin, Paul R.
中科院分区：
文献类型：
--
作者：
Delgado, Jary Y.;Nall, Duncan;Selvin, Paul R.
突触后密度蛋白95（post-synaptic density protein 95，PSD-95）在兴奋性突触发育和突触可塑性中起重要作用。PSD-95的N-末端在苏氨酸19（T19）和丝氨酸25（S25）处的磷酸化降低PSD-95在突触处的稳定性;然而，缺乏将PSD-95磷酸化与改变的突触稳定性联系起来的分子机制。在这里，我们表明，T19/S25的磷酸化招募磷酸化依赖的肽基脯氨酰顺反异构酶（Pin 1），并减少半胱氨酸3和半胱氨酸5的棕榈酰化PSD-95。PSD-95棕榈酰化的这种减少解释了所观察到的树突状PSD-95簇数量的减少、AMPAR迁移率的增加和功能性兴奋性突触数量的减少。我们发现Pin 1过表达的影响都被旨在增加PSD-95棕榈酰化水平的操作所挽救。因此，Pin 1是调节兴奋性突触稳定性的关键信号分子，并且可能参与突触可塑性诱导后PSD-95的不稳定化。
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.