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

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 S2 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 α3. 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.

Inhibition of the postsynaptic density protein 95 on the protective effect of Ang-(1-7)–Mas on cerebral ischaemia injury

“…PSD95 contains three PDZ domains. Through the different PDZ domains, PSD95 can interact with a variety of receptors containing PDZ-binding motifs to regulate the function of receptors 36. For example, PSD95 can regulate the potassium ion channel by binding to the KV1 receptor 37.…”

“…Through the different PDZ domains, PSD95 can interact with a variety of receptors containing PDZ-binding motifs to regulate the function of receptors. 36 For example, PSD95 can regulate the potassium ion channel by binding to the KV1 receptor. 37 PSD95 can inhibit the β1AR desensitisation by binding to the β1 adrenergic receptor.…”

Resonance assignment of the Shank1 PDZ domain

“…The role of the loops flanking the peptide binding site have been extensively discussed in the literature as they provide additional modulation to the partner binding properties by mediating allosteric effects (Mostarda et al 2012;Murciano-Calles et al 2014;Kumawat and Chakrabarty 2017;Kovács et al 2020). Comparative studies of the structure and dynamics of PDZ domains can reveal novel aspects of the common and unique features of PDZ domains, not directly available from the study of some common examples like the PSD-95 PDZ3 (Dudola et al 2020). Shank PDZ domains contain an unusually long β2-β3 loop (Supplementary Fig.…”

Interconnected Protein Networks: Insights Towards CRIB-Par6 Protein Allostery Through a Graph-Theoretic Analysis

“…Two well-studied PDZ domain families for investigating PDZ intradomain allostery are those of PDZ2 and PDZ3 wherein PDZ3 contains an additional c-terminal α3 helix. In analyses of PDZ3 domain containing systems like that of PSD-95, statistical coupling along with mutational studies investigating energetic couplings between residues with PDZdomains have identified differing networks of interactivity (Dudola, Hinsenkamp, & Gáspári, 2020). Many of these studies on PDZ3 highlight the particularly important energetic and structural coupling relationships between residues with the β2 and β3 strands and helix α2 (Gerek & Ozkan, 2011;Lockless Steve & Ranganathan, 1999).…”

“…Evidence for structurally-based allosteric modulation of ensemble state transition pathways have been demonstrated through principal component-based analysis of ensemble-state conformations of PSD-95 molecular dynamics simulations wherein viable transition pathways between ensemble states guided by internal side-chain structural rearrangements dominantly effect a motional coupling between the β1-β2 loop and the C-terminal part of the α2 helix, itself modulated by a secondary narrow-wide transition affecting the distance between the α2 helix and b2 sheet, which is, in turn, is modulated by the interactions with the additional a3 helix (Dudola et al, 2020). The role of conformational-coupling pathways between distal and binding site regions implicated by this dominant pathway are further corroborated by NMR-based relaxation based studies utilized by Fuentes et al in investigating coupled changes in HPTP1E side-chain dynamics upon ligand binding with the largest structural changes occurring at the protein-ligand interface at strand β2 and helix α2 (Fuentes, Der Cj Fau -Lee, & Lee, 2004) Mutational NMR-based studies have also revealed differences in structural ensemble-states of PDZ2 in ligand-bound complex and unbound form demonstrating subtle but nonetheless detectible ligand-induced, and thus inducedfit-based , coupled-conformational changes in mobility and rigidity involving the interface between the α2 helix and the β2 strand, and the β1-β2 loop and the hydrophobic core of the protein (Gianni et al, 2006).…”