Specificity in PDZ-peptide interaction networks: Computational analysis and review

Abstract

Globular PDZ domains typically serve as protein-protein interaction modules that regulate a wide variety of cellular functions via recognition of short linear motifs (SLiMs). Often, PDZ mediated-interactions are essential components of macromolecular complexes, and disruption affects the entire scaffold. Due to their roles as linchpins in trafficking and signaling pathways, PDZ domains are attractive targets: both for controlling viral pathogens, which bind PDZ domains and hijack cellular machinery, as well as for developing therapies to combat human disease. However, successful therapeutic interventions that avoid off-target effects are a challenge, because each PDZ domain interacts with a number of cellular targets, and specific binding preferences can be difficult to decipher. Over twenty-five years of research has produced a wealth of data on the stereochemical preferences of individual PDZ proteins and their binding partners. Currently the field lacks a central repository for this information.Here, we provide this important resource and provide a manually curated, comprehensive list of the 271 human PDZ domains. We use individual domain, as well as recent genomic and proteomic, data in order to gain a holistic view of PDZ domains and interaction networks, arguing this knowledge is critical to optimize targeting selectivity and to benefit human health.Amacher et. al.

Structural characterization and computational analysis of PDZ domains in Monosiga brevicollis

“…It would be interesting to test the target specificity of mbDLG-3 using a high throughput technique, for example, phage display or peptide arrays, in future experiments and/or to compare affinities with other known human Dlg4/PSD-95 PDZ3 ligands, for example, CRIPT, Stargazin, or Neuroligin, among other Dlg PDZ3 proteins. 26,37,57 Finally, we investigated a number of Dlg sequences in various organisms to see if there are others with an H-to-Y substitution at the αB-1 residue. None of the Dlg1 or Dlg2 (where available) sequences from Gallus gallus (chicken), Danio rerio (zebrafish), Callorhinchus milii (shark), Xenopus tropicalis (frog), Caenorhabditis elegans (worm), Anolis carolinensis (lizard), or Nematostella vectensis (sea anemone) contain a tyrosine residue at the αB-1 position (Figures 5C and S4D).…”

“…Specifically, the amide nitrogen atoms in the backbone of the GLGF-loop directly interact with the carboxylate atoms of the extreme C-terminus of a protein ligand. 25,26 PDZ domains are approximately 80-100 residues in length, and comparative analysis of hundreds of PDZ structures in the Protein Data Bank reveals a conserved structural fold, consisting of a core antiparallel β-sheet and 1-2 α-helices ( Figure 1). [26][27][28][29][30][31][32] PDZ domains are scaffolding domains that bind target proteins.…”

“…These PDZ domain interactions can be modulated by other protein-protein interaction domains on the same polypeptide, or in trans, by other proteins in larger macromolecular complexes. 26,33,34 An example of the scaffolding function of PDZ domains is the postsynaptic density of neurons, where multiple receptor signaling networks are brought into close physical proximity due to a number of PDZ domainmediated interactions. 35 As mentioned previously, an expansion of the number of PDZ domain-containing genes coincided with the emergence of animal multicellularity.…”

“…26 For example, Class I PDZ domains recognize the motif X-S/T-Xφ at the C-terminus of target proteins (where X = any amino acid and ϕ = any hydrophobic amino acid). 26 Work in the last 10+ years using high throughput techniques, for example, phage display, peptide array, or the hold-up assay, has shifted this classical view of PDZ domain binding to appreciate the importance of binding interactions at nonmotif residues in the peptide-binding cleft. [36][37][38] In addition, a number of elegant studies using directed evolution, or other protein engineering techniques, have successfully identified structural elements that determine PDZ selectivity-often through only a small number of amino acid substitutions or post-translational modifications.…”

Evolution of Modularity, Interactome and Functions of GIV/Girdin (CCDC88A) from Invertebrates to Vertebrates

“…Advantaged by their multi-modular makeup (Pawson and Nash 2003), they modulate the local concentrations of, proximity to, and subcellular dispositions and biochemical properties of the target proteins to impart plasticity within dynamic, spatially restricted intracellular signaling, earning them the reputation of 'placemakers' and 'pacemakers' of cell signaling (Pan, Sudol et al 2012). Among the numerous modules that facilitate scaffolding, PDZ domains [Post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and Zonula occludens-1 protein (zo-1)] comprises one of the largest, and is frequently encountered in proteins at the cell junctions (Amacher, Brooks et al 2020). PDZ binding motifs (PBMs) are short linear motifs commonly found on the C-terminus of proteins (although internal PBMs do exist) and mediate the PDZ•PBM interactions.…”