PDZ/PDZ interaction between PSD‐95 and nNOS neuronal proteins

Abstract

N‐Methyl‐D‐aspartate (NMDA) receptors are key components in synaptic communication and are highly relevant in central nervous disorders, where they trigger excessive calcium entry into the neuronal cells causing harmful overproduction of nitric oxide by the neuronal nitric oxide synthase (nNOS) protein. Remarkably, NMDA receptor activation is aided by a second protein, postsynaptic density of 95 kDa (PSD95), forming the ternary protein complex NMDA/PSD95/nNOS. To minimize the potential side effects derived from blocking this ternary complex or either of its protein components, a promising approach points to the disruption of the PSD‐95/nNOS interaction which is mediated by a PDZ/PDZ domain complex. Since the rational development of molecules targeting such protein‐protein interaction relies on energetic and structural information herein, we include a thermodynamic and structural analysis of the PSD95‐PDZ2/nNOS‐PDZ. Two energetically relevant events are structurally linked to a “two‐faced” or two areas of recognition between both domains. First, the assembly of a four‐stranded antiparallel β‐sheet between the β hairpins of nNOS and of PSD95‐PDZ2, mainly enthalpic in nature, contributes 80% to the affinity. Second, binding is entropically reinforced by the hydrophobic interaction between side chains of the same nNOS β‐hairpin with the side chains of α2‐helix at the binding site of PSD95‐PDZ2, contributing the remaining 20% of the total affinity. These results suggest strategies for the future rational design of molecules able to disrupt this complex and constitute the first exhaustive thermodynamic analysis of a PDZ/PDZ interaction.

Nitric oxide signaling in ctenophores

“…Second, Mnemiopsis leidyi NOS lacks the PDZ domain, found in many NOSs from poriferans (desmosponges Halisarca , Spongilla , and Amphimedon , but not from the calcareous sponge Sycon ciliatum ), Placozoa ( Trichoplax ), cnidarians (corals, sea anemones), and bilaterians/chordates ( Figures 1 , 2 ). PDZ domain is best studied in mammals and is responsible for anchoring neuronal NOSs in specific membrane compartments and protein complexes, facilitating more localized and spatial control of NO release and signaling in synapses ( Brenman et al, 1996 ; Stricker et al, 1997 ; Jaffrey et al, 1998 ; Kim and Sheng, 2004 ; Feng and Zhang, 2009 ; Sheng et al, 2018 ; Murciano-Calles et al, 2020 ). Of note, PDZ NOSs were not found in non-metazoan eukaryotes and prokaryotes and can be viewed as animal innovation coupled with their morphological and signaling complexities.…”

The Conformational Plasticity Vista of PDZ Domains

“…The case of the PDZ-PDZ interaction between nNOS and PSD95 [78], which is key in numerous neuronal functions [79][80][81][82], is similar. nNOS-PDZ/PSD95-PDZ2 complex is known to have an interdomain β-sheet arrangement formed by two β-strands from PSD95-PDZ2 and a β-finger in nNOS [83,84] considered as an extra-structure of the canonical PDZ fold. Jemth's group analyzed the binding kinetics to decipher if the β-finger in nNOS-PDZ comprises an ensemble of conformations previous to the interaction since this extra-structural element is better arranged upon binding.…”

Molecular Characterization of a Novel Shell Matrix Protein With PDZ Domain From Mytilus coruscus

“…CLP-2 is a vWA (von Willebrand factor type A) domain-containing SMP, and the vWA domain was reported to show accessibility for intermolecular interactions during mollusk shell formation (Chang and Evans, 2015). Whirlin is a PDZ domain-containing SMP, and the interaction of PDZ-PDZ was previously confirmed (Sotelo et al, 2015;Murciano-Calles et al, 2019). In addition, two Ser-rich SMPs (SD-rich protein-1 and SKrich protein-1) were identified from the pulled down proteins.…”