<h3>Title</h3>
<p><span style="color: #0000ff;">Conformational Dynamics and Supertertiary Structure of Multi-domain  Scaffold Protein, PSD-95</span></p>
<p><strong><span style="text-decoration: underline;">Abstract</span> :</strong></p>
<p>PSD-95 (Postsynaptic density protein 95) is a scaffolding protein in the excitatory synapse that connects proteins involved in neurotransmitter release. The interdomain organization within the supertertiary structure of PSD-95 reveals two independent supramodules, PDZ1-PDZ2 tandem and PDZ3-SH3-GuK (PSG) core, which gives rise to its dynamic supertertiary structure. Supertertiary interactions between these domains have been suggested to regulate their binding activity although structural models for the PSG vary widely. Here we characterize the structure and dynamics of the PSG supramodule using a combination of discrete molecular dynamics simulations and single molecule FRET experiments with time resolution spanning picoseconds to seconds. We measured a FRET network of 12 variants in full-length PSD-95, which we used in rigid body modeling to map out the supertertiary landscape. PDZ3 samples two conformational basins, which were confirmed with disulfide mapping. PDZ3 showed a fuzzy electrostatic interaction with the SH3<sub>HOOK</sub> insertion along with a secondary binding site on GuK that allowed for a wide range of conformations including some involving the binding face of PDZ3. Truncation of PSD-95 to the PSG, showed increased dynamics but did not disrupt interdomain interactions. The research findings are proposed to be significant in characterizing the conformational dynamics of PSD-95, understanding its role in the downstream regulation of signal transduction pathways, and identifying the long-term critical effects of posttranslational modifications.</p>
<p><u>Selected publication:</u></p>
<p>1. George Hamilton, Nabanita Saikia, Sujit Basak, Franceine S. Welcome, Yan Hao, Fang Wu, Jakub Kubiak, Claus A.M. Seidel, Feng Ding, Hugo Sanabria, Mark E. Bowen. Fuzzy Supertertiary Interactions within PSD-95 Enable</p>
<p>    Ligand Binding (submitted).</p>