Abstract
Phosphorylation-dependent peptidyl-prolyl cis-trans isomerization plays key roles in cell cycle progression, the pathogenesis of cancer, and age-related neurodegeneration. Most of our knowledge about the role of phosphorylation-dependent peptidyl-prolyl cis-trans isomerization and the enzyme catalyzing this reaction, the peptidyl-prolyl isomerase (Pin1), is largely limited to proteins not present in neurons. Only a handful of examples have shown that phosphorylation-dependent peptidyl-prolyl cis-trans isomerization, Pin1 binding, or Pin1-mediated peptidyl-prolyl cis-trans isomerization regulate proteins present at excitatory synapses. In this work, I confirm previous findings showing that Pin1 binds postsynaptic density protein-95 (PSD-95) and identify an alternative binding site in the phosphorylated N-terminus of the PSD-95. Pin1 associates via its WW domain with phosphorylated threonine (T19) and serine (S25) in the N-terminus domain of PSD-95 and this association alters the local conformation of PSD-95. Most importantly, I show that proline-directed phosphorylation of the N-terminus domain of PSD-95 alters the local conformation of this region. Therefore, proline-directed phosphorylation of the N-terminus of PSD-95, Pin1 association, and peptidyl-prolyl cis-trans isomerization may all play a role in excitatory synaptic function and synapse development.
Highlights
The postsynaptic density (PSD) of excitatory synapses is a highly crowded space composed of transsynaptic proteins, extracellular matrix constituents, surface receptors, ion channels, and scaffolding proteins
The sequence alignment showed that threonine 19 (T19), serine 25 (S25), and serine 35 (S35) contain many of the amino acids found in most Pin1 binding partners (Figure 1A right)
The T19/S25 phosphorylated form of PSD-95 enriches, biochemically, to the PSD fraction II, but lower amounts can be detected in the PSD fraction number III (Morabito et al, 2004)
Summary
The postsynaptic density (PSD) of excitatory synapses is a highly crowded space composed of transsynaptic proteins, extracellular matrix constituents, surface receptors, ion channels, and scaffolding proteins. PSD-95 is a rather stable element of the PSD, capable of sustaining harsh biochemical extractions, PSD-95 synaptic stability is regulated following the induction of synaptic plasticity (Migaud et al, 1998; Colledge et al, 2003; Sun and Turrigiano, 2011). The induction of synaptic plasticity, namely NMDAR-dependent long-term depression (LTD), increases the phosphorylation state of the N-terminus domain of PSD-95 and this event regulates its stability, Pin1-Mediated Isomerization of the N-Terminus Domain of PSD-95 clustering, proteolytic cleavage, and PSD-95 palmitoylation (Colledge et al, 2003; Morabito et al, 2004; Xu et al, 2008; Nelson et al, 2013; Zhang et al, 2014; Chowdhury et al, 2018). Despite significant advances on this topic, there is a lack information about potential binding partners interacting with phosphorylated T19 and S25 in PSD-95 that may regulate the stability following its increase in phosphorylation
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