Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures.

Dániel Dudola,Zoltán Gáspári,Anett Hinsenkamp

doi:10.3390/ijms21218348

Dániel Dudola, Zoltán Gáspári + Show 1 more

Open Access

https://doi.org/10.3390/ijms21218348

Copy DOI

Abstract

PDZ domains are abundant interaction hubs found in a number of different proteins and they exhibit characteristic differences in their structure and ligand specificity. Their internal dynamics have been proposed to contribute to their biological activity via changes in conformational entropy upon ligand binding and allosteric modulation. Here we investigate dynamic structural ensembles of PDZ3 of the postsynaptic protein PSD-95, calculated based on previously published backbone and side-chain S order parameters. We show that there are distinct but interdependent structural rearrangements in PDZ3 upon ligand binding and the presence of the intramolecular allosteric modulator helix 3. We have also compared these rearrangements in PDZ1-2 of PSD-95 and the conformational diversity of an extended set of PDZ domains available in the PDB database. We conclude that although the opening-closing rearrangement, occurring upon ligand binding, is likely a general feature for all PDZ domains, the conformer redistribution upon ligand binding along this mode is domain-dependent. Our findings suggest that the structural and functional diversity of PDZ domains is accompanied by a diversity of internal motional modes and their interdependence.

Highlights

The postsynaptic density (PSD) of excitatory synapses is a well organized, dynamic network of proteins involved in processes of synaptic plasticity, learning and memory [1]
The conformational space explored by the different ensembles was analyzed in order to gain insight into the dynamical changes occurring upon ligand binding in the full and truncated forms
To inspect the effects of side-chain order parameter restraining, exploratory simulations were carried out using different combinations of parameters available for PDZ3

Summary

Introduction

The postsynaptic density (PSD) of excitatory synapses is a well organized, dynamic network of proteins involved in processes of synaptic plasticity, learning and memory [1]. PSD-95 is the most abundant scaffold protein of the PSD taking part in a multitude of protein–protein interactions within the network [2]. It is involved in mechanisms/procedures including the stabilization, recruitment and trafficking of AMPA receptors to the postsynaptic membrane and dendritic spine morphogenesis during neurodevelopment, as well as in glutamatergic transmission and synaptic plasticity. PSD-95 and related MAGUK proteins have been suggested to have two supramodular parts, the PDZ1-2 tandem and the PDZ3-SH3-GK domain unit. The PDZ1-2 tandem was shown to exhibit altered interdomain dynamics upon ligand binding [3]. Models of the supertertiary structure of this supramodule suggest interactions between the PDZ3 and SH3 domains as well as a phopshorylation-dependent binding of a linker segment into the peptide binding groove of PDZ3 [6,7]

Methods

Results

Discussion

Conclusion