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

• Published in: Journal of structural biology. X 2020-01, Vol.4, p.100022-100022, Article 100022
• Main Authors: Amacher, Jeanine F., Brooks, Lionel, Hampton, Thomas H., Madden, Dean R.
• Format: Article
• Language: English
• Subjects: PDZ; Peptide-binding domains; Protein-protein interactions; Therapeutic targets
• ISSN: 2590-1524; 2590-1524
• DOI: 10.1016/j.yjsbx.2020.100022

[Display omitted] •A list of the PDZ domains in the human proteome, including associated names and other domains.•A list of all mammalian PDZ domain-containing entries (total: 468) in the PDB.•Statistical analyses of binding affinities from for both endogenous and engineered sequences.•An extensive review of the PDZ selectivity literature over the past 25 years. 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.